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有机合成化学


高等有机合成 Advanced Organic Synthesis

绪 论
一、有机合成的历史回顾
二、有机合成化学的发展趋势 三、学习内容和方法 四、重要参考书及期刊 五、课程安排

一、有机合成的历史回顾
1. 尿素的合成 (1828年,德国化学家 Wohler)
O NH 4OCN H2 N NH2

有机化学的开始

2. 颠茄酮的合成
1) 1902年,德国化学家 Willstatter (1915年获Noble 化学奖)

21 steps, overall yield 0.7%

2)1917年,英国化学家 Robinson (1947年获Noble 化学奖)

3 steps, overall yield 90% Robinson为什么能是发现这条合成路线?
R
1

R NH + HCHO +

3

R3 O R
4

R1 N R2 R4

O

R2

Mannich Reaction (1912)

3. 维生素B12 的合成 (Woodward, 1977年)
因在1945-1954年人工合成了奎宁、类固醇、 马钱子碱、羊毛甾醇、麦角碱等近20种复杂天然 产物而1965 年获Noble 化学奖

在Woodward及Eschenmoser 领导下, 经过两个 实验室,100多位科学家的共同努力,于1977年完成 了维生素B12的全合成工作。
将有机合成作为一种艺术展现在世人面前。

4. E. J. Corey, (1990年获Noble 化学奖) 逆合成分析 (Retrosynthetic analysis) 如果说Woodward 一生奋斗的成就是将有机合成 作为一种艺术展现在世人面前,那么Corey 则是将 有机合成从艺术转变成为科学的一个关键人物。他 的逆合成分析是现代有机合成化学的重要基石,推 动了20世纪70年代以来整个有机合成领域的蓬勃发 展。

? Woodward (1981) 红霉素的全合成 ? Y. Kishi (1987) 海葵毒素的全合成 ? S. L. Schreiber et al (1993) FK-1012 的全合成 ? K. C. Nicolaou & S. L. Schreiber(1994) 紫杉醇(Taxol)的全合成

5. K. C. Nicolaou & S. L. Schreiber
? K. C. Nicolaou, et al. The art and science of total synthesis at the dawn of twenty-first century, Angew. Chem. Int. Ed. Engl., 2002, 39, 44 ? S. L. Schreiber, et al. Target-oriented and diversityoriented organic synthesis in drug discovery, Science, 2000, 287,1 964 高立体选择性 (High Stereoselectivity) 原子经济性反应 (Atom Economical Reaction) 绿色化学 (Green Chemistry)

二、有机合成化学的发展趋势
1. 新试剂、新反应、新方法的发现永无止境 ? Epibatidine(地棘蛙素) 的研究
ED50: 0.005 mg/kg s.c. 1.5 mg/kg i.p. in mice, hot plate test Ki: (+) 0.045nM; (-) 0.058 nM, nAChR isolated from skins of the Ecuadoran poison frog Epipedobates tricolor Daly, John W. etal. J. Am. Chem. Soc. (1992), 114(9), 3475-8

H N

N

Cl

Epibatidine

First total synthesis of (+)and (-)-EP Corey, E. J. et al. USA. J. Org. Chem. (1993), 58(21), 5600-2.

First patent: Daly, John W. et al. US 845042(1993)

General Introduction of Epibatidine

NR R" + N R R' R" NBoc H NBoc + SO2Tol SO2Tol R"

NR R" + N R R' R"

R"

R" + N R' Y(OTf)3 N R"

R"

? Y(OTf)3-catalyzed novel Mannich reaction of N-alkoxycarbonylpyrroles, formaldehyde and primary amine hydrochlorides
R' N N R" Y(OTf)3 (10%mmole) A R' CHNHR" N R B

+ R'CHO + R"NH2 . HCl N R

C. X. Zhuan, J. C. Dong, T. M. Cheng, R. T. Li*, Tetrahedron Letters, 2001, 43(3), 461-463

? Aldol 缩合反应的研究
OH经典的方法 R' RCHO + R'CH2CHO TiCL4 定向 Aldol 缩合 RCHCHCHO OH L-Proline 有机小分子催化

2. 与生命科学和材料科学的联系越来越紧密
组合化学 Combinatorial Chemistry

药物化学 Medicinal Chemistry

材料科学 Material Sciences

三、学习内容和方法
? 内容
C-C单键的形成 分子骨架的形成 C-C双键的形成 反应的学习 氧化反应 官能团之间的转换 还原反应 取代反应 反应的应用 (有机化合物合成路线设计)

有机合成

?

方法

1. 对重要的基础有机反应要能够熟练运用 比葫芦画瓢 新化合物的合成 逆合成分析 2. 跟踪文献,尽可能将最新的试剂、反应和方法应用于 自己的研究工作中。 3. 学习别人的思路,创造性地借鉴和运用

四、重要参考书及期刊
? 参考书 1. 2. 3. F. A. Carey 著,王积涛译,高等有机化学, B. 反应与 合成,高 等教育出版社,1986。 岳保珍,李润涛,有机合成基础,北京医科大学出版社,2000。 吴毓林,姚祝军,现代有机合成化学,科学出版社,2001。

4.
5.

W. Carruthers 著,李润涛等译,有机合成的一些新方法,河南大 学出版社,1991。
黄宪,王彦广,陈振初,新编有机合成化学,化学工业出版社, 2003。

6.
7.

王咏梅等,高等有机化学习题解答,南开大学出版社,2002。
Dale L. Boger, Modern Organic Synthesis, The Scripps Research Institute, Tsri Press, 1999.

8.

Comprehensive Organic Synthesis, Vol. 1-9

? 期刊 1. 2. Angew. Chem. Int. Ed. J. Am. Chem. Soc. 11. Synth. Commun. 12. Eur. J. Chem.

3.
4. 5.

J. Org. Chem.
Org. Letters Chem. Commun.

13. Eur. J. Org. Chem.
14. Heterocyclics 15. J. Heterocyclic Chem.

6.
7. 8.

Tetrahedron
Tetrahedron Letters. Tetrahedron Asymm.

16. J. Med. Chem.
17. Bioorg. Med. Chem. 18. Bioorg. Med. Chem. Lett.

9.

Synthesis

19. Eur. J. Med. Chem.
20. J. Comb. Chem.

10. Synlett

五、课程安排
1. 进度安排

2. 讲授原则 复习老反应,补充新反应, 重点讲进展,强调学思路。 3. 考试

笔试

Chapter 2 Formation of Carbon-Carbon Single Bonds

一、General Principles
A CH B H B A CH E+ A CH B E

Base

烷化反应: E = 烷化剂
缩合反应: E = 醛、酮、酯等 Michael 加成:E = Mannich 反应

~

EWG

二、影响反应的主要因素 a. 反应底物 (Substrate)

A B CH2

A和B应该能使其 ?-碳上的H活化的基团,通常为吸电子 基(Electron withdraw group EWG)。

-NO2 > -COR > SO2R > -CN > -CO2R > -Ph , SOR
A和B至少要有一个是 EWG

b. 碱 (Base)
理想的碱:碱性强,亲核性弱,并不进攻那些较敏感的基团,另外 能溶于非极性溶剂中。 常用的碱: Ph3C- > (Me2CH)2N- > EtO- > OH- > R3N 碱的选择取决于底物的反应活性

c. 溶剂 (Solvent) O- alkylation C-alkylation Solvent
反应速度

常用的非质子极性溶剂 (polar aprotic solvent): DMF DMSO
O Me2N P NMe2 NMe 2

HMPA

d. 亲电试剂 (Electrophilic reagent)
所有能与负碳离子发生反应的碳正离子或分子。 例: RX, R-SO3H, RCO2Et, RCOR’
R R 反应速度 R R OTs Cl Br I Solft alkylating agent Hard alkylating agent

这四种影响因素之间是相互联系,相互影响的。在分析 一个具体反应时,应该综合分析考虑这四种影响因素。

三、烷基化反应 (Alkylation) 1. O-alkylation & C-alkylation
O O

Example 1

Example 2

Degree of substitution of alkylating agent:

2. 区域选择性 (Regioselectivity)
区域选择性受热力学控制和动力学控制的反应条件影响 很大.

热力学控制条件下主要生成取代基较多的烯醇; 动力学控制条件下主要生成取代基较少的烯醇;
Example 1

Example 2

3. 立体选择性 (Steroselectivity)

烯醇化合物的立体选择性形成, 将为不对
称合成提供平台.

Example 1

Example 2

Example 3

4. 二羰基化合物的 ? -烷基化反应 ( ?-Alkylation of 1, 3dicarbonyl compounds)
O R O R' 2 equiv. Base R O O R' O 1) R"X 2) H2O R" R O R'

J. Am. Chem. Soc., 1974, 90, 1082; 1963, 85, 3237; 1965, 87, 82.

Example 1
O Me O Me 1) 2 KNH2 / liq. NH3 2) n-BuBr
O O Me O Me Me 烷基化难易次序: PhCH2- > CH3- > -CH2-

O Me

O C4H9 82%

Example 2
O Me O OEt 1) 1 equiv NaOH / THF / HMPA 2) 1 equiv. n-BuLi O O OEt OTHP Br O O O 1) 2 equiv. LDA 2) C6H5SeBr O O O SeC6H5 1) H2O2, CH2Cl2, 0o C 2) - 25oC O diplodialide A O O severial steos O O OEt OTHP

5. 芳基卤化物与烯醇盐的反应 (Reactions of aromatic halide with enolates)
Example
CO2Et + CO2Et CO2Et 过量 NaNH2 liq. NH3

C6H5 Br

C6H5
CO2Et

Mechanism
CO2Et Br CO2Et CO2Et CO2Et

NaNH2 liq. NH3

CO2Et CO2Et

H3O

+

CO2Et CO2Et

6. 酮和酯的烷基化反应 (Alkylations of ketones and esters)
a
R Y X R CO2R' O
R

b
R'

RX

常用的碱:NaNH2, KNH2, NaH, Ph3CNa 等;有副产物。

~ ~

~
O

~
Aldol Condensation

~
O

~
O

避免Aldol 缩合反应发生的方法:

~

~

~

~
OH O

烷化剂要待酮完全转化为烯醇式后再加入。

LDA, LTMP, LHMDS 等效果很好。

Example 1
O 1) NaNH2 / C6H6, Reflux C6H5 2) Br C6H5 88 % O

Example 2

1) LDA / THF, - 78 o C CO2Me 2) Br CO2 Me

1) LDA / THF, - 78 o C 2) Br CO2Me

90 %

? 不对称酮的选择性烷基化反应 (Selective alkylation of asymmetric ketones)
a R O b R'

? 在一个?? - 位引入一个活化基 (略)

如: Dieckmann Reaction; Claisen condensation
? 制成结构专属性的烯醇负离子

? 在取代基较多的 ? - 位烷基化 (烯醇硅醚法)
O Me 1) NaH /GDME 2) Me3SiCl / Et3N 78% 22% Me OSiMe3 + Me OSiMe3

碱性条件
OSiMe3 Me MeLi / GDME 25 C OLi Me C6H5 CH2Cl Me + C6H5 84% 7% O Me C6H5 O
o

OLi Me + Me4Si

酸性条件
XMe3SiO R1 R
2

RX Lewis acid

Me3 SiO R1 R

R2 R3 R1

O

R2 R3 R

R3

Lewis acid: TiCl4, SnCl4, ZnCl2

OSiMe3 Me

O 1) t-BuX / TiCl4 CH2Cl2 / - 23 oC 2) Na2CO3 Me Me Me Me 48%

? 在取代基较少的 ? - 位烷基化 (烯胺法, Stork Enamine Synthesis)
O

NH

N

N

N-alkylation

E+

C-alkylation

? 通常,用活泼的卤代烷,可以高产率生成C-烷基化产物; 但对于一般的卤代烃, C-烷基化产物收率较底。若用 LDA在低温下反应,则对各种卤代烃均可得到高收率的 C-烷基化产物。 ? 对于不对称酮,主要在取代基较少的 ? - 位发生烷基化。

Example 1
O N + Cl H3O + 96%

Example 2
1) LDA DME / - 60oC 2) MeI 3) H3O+ O

O

N H

N

98%

7. 极性翻转(Umpolung)
? 俞凌翀,刘志昌,极性转换及其在有机合成中的应 用,科学出 版社,1991 Example 1 安息香缩合
-

O C 6H 5 C H CN

C6H5CHO

CN

OH C6H5 C CN

C6H5 CHO

OH O C6H5 C C C6H5 CN H

- CN-

O C6 H5 C

OH C C6 H5 H

Example 2 醛氰醇法

CH3CHO

CN -

OH CH3 C CN

Me3SiCl

OSiMe3 C6 H5 CH CN

1) LDA 2)

Br

OSiMe3 CH3 C CN H3O

OH CH3 C CN OH CH3

O C 85%

Example 3 1, 3 –二噻烷法

SH + SH RCHO

HCl / CH3Cl

S S

H R

BuLi

S S

Li R

R'X

S S

R' R

H3O+ / Hg 2+

R' O R

不易发生Michael 加成反应。

四、缩合反应 (Condensation) 1. Aldol Reaction 2. Michael Addition 3. Mannich Reaction 4. Claisen Condensation

5. Dieckmann Condrnsation
6. Darzen’s Reaction 7. Reformatsly reaction

1. Aldol Reaction (condensation) 1) 经典Aldol 反应的两大缺点 ? 不同醛、酮之间的反应常得到混合产物; ? 立体选择性差

2) 定向醇醛缩合反应 (Directed Aldol condensation) Metood 1 Preformed Lithium Enolates

? Z-enolates give predominantly syn (or threo) aldol products (thermodynamic enolates).

? E-enolates give predominantly anti (or erythro) aldol products (kinetic enolates).

Example 1

- Steric size of R1 affects diastereoselectivity

Method 2 Preformed Boron Enolates

a. Z-enolate Preparation and Reactions

b. E-enolate Preparation and Reactions

Aldol Condensation with Chiral Enolates

? Ti enolate promoted Evans aldol (non-Evans syn aldol)

Metood 3 Acid-Catalysed Directed Aldol Reactions
R3 R
1

OSiMe3 R3

TiCl4 CH2 Cl2 R2 R1 R4

O

ClSiMe3 TiCl3 Cl O R5

R2

- Me3SiCl

R3

O H2 O OH R
4

R3

O TiCl3 O R4 R5

R2 R1

R2 R1

该方法是 在酸性条件 下反应;但 立体选择性 较差。

R5

3) 有机小分子催化醇醛缩合反应 (Small Organic Molecules Catalysted Aldol Reactions)
O
Aldolase Antibody 38C2 Barbas, C. F., III et al. J. Am. Chem. Soc. 1997,119, 8131

O O O
L-Proline

O O

Hajos-Eder-Sauer-Wiechert reaction Hajos, Z. G. et al. J. Org. Chem. 1974, 39, 1615 Eder, U.; Sauer; G., Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496

However, the proline-catalyzed direct intermolecular asymmetric aldol reaction has not been described. Further, there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism.Based on our own results and Shibasaki's work on lanthanum-based small-molecule aldol catalysts, we realized the great potential of catalysts for the direct asymmetric aldol reaction.

O

O + H NO2

L-proline 30mol% DMSO

O

OH

NO2 68% (76% ee)

O

O + H NO2

different amino acid 30mol% DMSO

O

OH

NO2

L-proline is best O O + H R L-proline 30mol% DMSO yield: 54-97%; % ee: 60-96% O OH R

+ HN

O

H O HO

N
a

H - H 2O O
b

N

+

H
c

N HO

H O

OH

HO

-O O

RCHO
d

R H R

O

N O H

H R O e OH

N

+

H H 2O R f OH

-O O

H + N O H OH -O

g

OH

O

+ HN

H O HO

Proposed Enamine Mechanism of the Proline-catalyzed Asymmetric Aldol Reaction

Carlos F. Barbas III et.al. J. Am. Chem. Soc. 2000, 122(10), 2395-6

Catalytic Asymmetric Synthesis of anti-1,2-Diols
O + H OH R O O L-Proline 20-30mol% DMSO r. t. 24-72h OH

OH

syn:anti: 15:1-20:1; yield: 38-95%; % ee: 67-99% Carlos F. Barbas III et.al. J. Am. Chem. Soc. 2000, 122(30), 7386-7

Proline-Catalyzed Asymmetric Aldol Reactions between Ketones and a-Unsubstituted Aldehydes
O + H 20 vol% O R L-Proline 10-20mol% CHCl3 3-7 d O OH R + A B O R

yield: A 22-35%, B 35-50%; % ee: 36-73% O O L-Proline R L-Proline O OH R A O R B - Proline O N CO2H R H R + N H O CO2-

Compound B wasformed via Mannich Condensation
Benjamin list et al. Org. Lett. 2001, 3(4), 573-575

The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes

O R R' + ArC HO amino acid R

O

OH Ar R'

Barbas, C. F. etal. J. Am. Chem. Soc. 2001, 123(22), 5260-5267

O H X + H

O enantioselective catalyst Y H

O

OH

X

Y

O H Me

N CO2H H 10mol % DMF, 4 C
o

O H Me

OH Me

80% yield, 4:1 anti:syn, 99% ee

O H R1 + H

O R2

10mol % L-proline DMF, 4oC yield: 75-88% H

O

OH R2 R1

anti:syn: 3:1-24:1 % ee: 91:99

MacMillan D. W. C. et al. J. Am. Chem. Soc. 2002, 124(24), 6798-6799

Novel Small Organic Molecules for a Highly Enantioselective Direct Aldol Reaction
Zhuo Tang,?,? Fan Jiang,§ Luo-Ting Yu,? Xin Cui,? Liu-Zhu Gong,*,? Ai-Qiao Mi,?Yao-Zhong Jiang,? and Yun-Dong Wu*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, College of Chemical Engineering, Sichuan UniVersity, Chengdu, 610065, China, and State Key Laboratory of Molecular Dynamics and Stable Structures, College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing, 100871, China

J. AM. CHEM. SOC. 2003, 125, 5262-5263

2. Michael Addition Reaction
? General Scheme
EWG R' CH2 + R "R R'" EWG' :B CH R C R" CH R'" GWE R' EWG'

EWG, EWG' = -CHO, -CO-, -COR, -CN, -NO2, -SO2R et al.

? Applications: Synthesis of 1,5-dicarbonyl compounds

? Development: Asymmetry Michael Addition Reaction
? 手性金属配位化合物催化
O CO2Bn + CO2Bn 10 mol % Li-Al-(R)-BiNol THF, r. t., 72 h CH(CO2Bn)2 88%, 99% ee O

H

Arai T. et al., Angew. Chem. Int. Ed., 1996, 35, 104

? Small Organic Molecule catalyzed asymmetric Michael reactions
Macmillan Group’s Work

R + 20mol % A-HCl O 23oC yiled: 72-90%; % ee: 83-96% CHO

X

R

X

Diels-Alder Reaction
J. Am. Chem. Soc. 2000, 122(17), 4243-4244 X N R 20mol % A-TFA O N N H Me Me Me X N R Z
O

+

Z

O

THF-H 2O

Ph

A

yiled: 74-87%; % ee: 89-97% Z +N O R1 R + O
20mol % A-HClO4 MeNO2-H 2O -20 C
o

Z N O R CHO endo R1 +

Z N O R R1

J. Am. Chem. Soc. 2001, 123(18), 4370-4371

% ee: 90-99% yield: 66-98%

CHO exo endo:exo: 80:20-99:1

1,3-Dipolar Cycloaddition
J. Am. Chem. Soc. 2000, 122(40), 9874-9875

X N R

+

Z

O

20mol % A-TFA THF-H2O 74-87% 91-99% ee

X N R Z

O J. Am. Chem. Soc. 2001, 123(18), 4370-4371

Me + N Me Me O 20mol % A-TFA CH2Cl2, -40oC 85% 56% ee O N Me Me N Me Ph N H B Me Me O

O

Me N N H A Me Me

Ph

Me + N Me Optimal conditions: Me O 20mol % B-HX solvent N Me HX = TFA Solvent: CH2Cl2-i-PrOH R + N Me R O 20mol % B-TFA CH2Cl2-i-PrOH 74-89% > 90% ee Z + Me N R 20mol % B-TFA O CH2Cl2-i-PrOH 70-94% > 89% ee Y N R N Me O O

Z

Me O

Y

Joel F. Austin and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124(7), 1172-1173

3. Mannich Reaction
? General Scheme
R R1 NH + O R2CH + O R3CH2CR4 H+ R R1 R2 R3 O

NCHCHCR4

?

胺组份

氨、伯胺、仲胺

可分别发生三、双、单 Mannich 反应 ? ? 醛组份 活泼 H 组份 醛、 酮、 活泼亚甲基化合物、酚类化合物、杂环、炔等。 HCHO, PhCHO, RCHO

Example 1
Me H NHMe HCHO O Me H O N Me

Example 2
O + HCHO + HNMe2 O O O OEt Michael addition O H3C CO2Et Aldol reaction O . HCl O NMe2

CO2Et O

1) OH 2) H + / - CO2 O

? Development: Asymmetry Mannich Reaction ? Lewis acid-catalyzed asymmetric Mannich reactions
(a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450; (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180; (c) Ishihara, K.; Miyata, M.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520; (d) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 2060; (e) Ferraris, D.; Yong, B.; Dudding, T.; Leckta, T. J. Am. Chem. Soc. 1998, 120, 4548; (f) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67.

(g) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640.

? Small Organic Molecule catalyzed asymmetric Mannich reactions

(a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 199; (b) Juhl, K.; Gathergood, N.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995; (c) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857; (d) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (e) Co?rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1842; (f) Co?rdova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866.

The Direct Catalytic Asymmetric Three-Component Mannich Reaction
NH-PMP

O +

CHO +

NH2 L-Proline 35mol% DMSO r. t. 12h 50%

O

OMe

94% ee

O + H R= NO2 i-Pr-

O R

L-Proline 35mol%

O

NH-PMP

p-anisidine(1.1eq.)
DMSO 12-48h yield: 35-90%; ee: 73-96% n-BuR

i-Bu-

O + R1 R2

CHO +

NH2 L-Proline 35mol% DMSO r. t. 12h 50%

O

NH-PMP

OMe

R1

R2

a. R1= H, R2=Me, 99% ee;

R1= Me, R2=H, 94% ee; total yield 96%

b. R1 = H, R2= OMe, 98%ee, yield 93%

Benjamin List . J. Am. Chem. Soc. 2000, 122(38), 9336-7

The Direct and Enantioselective, One-Pot, ThreeComponent, Cross-Mannich Reaction of Aldehydes

Y. Hayashi,W. Tsuboi, I. Ashimine, T. Urushima,Dr. M. Shoji
Department of Industrial Chemistry, Faculty of Engineering

Tokyo University of Science, Kagurazaka

Angew. Chem. Int. Ed. 2003, 42, 3677 –3680

Three-component Mannich reaction with various acceptor aldehydes
N-methyl-2pyrrolidinone (NMP)

Three-component Mannich reaction with various donor aldehydes.

4. Claisen Condensation
? General Scheme
O B: 2RCH2CO2 Et RCH2CCHCO2Et R

? Mechanism
H O RCHCOEt B: O H O

RCHCOEt + RCHC OEt O RCH 2CCHCO2Et R

H ORCHC OEt RCHCOEt O - EtO

-

? Scope of application ? 一种酯的自身缩合 ? 一种含 ?-H 的酯与一种不含 ?-H的酯之间的缩合 ? Examples
CO2Et N + EtCH2CO2Et NaH N
Ph CO2Et CO2Et EtONa + PhCH2CO2Et EtOH CO2Et Ph CH CO2Et COCHCO 2Et CO 2Et

COCHCO2Et Et

- 175 oC - CO

? Directed Claisen condensation

RCH2CO2Et

LDA

RCHCO 2Et

R'COCl

RCHCO2Et COR'

5. Dickmann Condensation
CO2Et (CH 2)n CO2Et 分子内Claisen 缩合反应 B: (CH2)n-1 O CO2Et

Li N

CO 2Me O CO2Me CO2Me

Chapter 3 Formation of Carbon-Carbon Doule Bonds

I. The Synthetic Methods of Alklenes
1. ?-Elemination reactions (?-消去反应)

C H

C X

C

C

+

HX

X = -OH, -OCOR, 卤素, -OSO2Ar, -N+R3, -S+R2 et al.

Saytzeff rule Regioselectivity Hofmann rule

X = -OH, -OCOR, 卤素, -OSO2Ar, X = -N+R3, -S+R2

Syn elimination Saytzeff eliminations Stereoselectivity Anti elimination

Hofmann eliminations

Anti elimination

2. Pyrolytic syn eliminations(顺式热消去反应)

C H O

C O

300 ~ 500 C

o

C

C

+

RCO2 H

R

Applications: Synthesis of terminal alkenes from primary acetates
CH3CH2CH2CH2OCOCH3 500oC N2 CH3CH2CH=CH2

100%

Disadvantages: High reaction temperature

O C H S SR C O
o

C

C

+

HSCSR

100 ~ 200 C

Chugave reaction

C H O

C NR2

100 ~ 200oC

C

C

+

R2NOH

Cope reaction

反应条件比对应的酯热消去温和。

3. Wittig and related reactions (Wittig 及有关反应)
? Wittig Reaction

G. Wittig received the 1979 Nobel Prize in Chemistry for "many significant contributions to Organic Chemistry" which included not only the Wittig reaction, but also PhLi prepared by metal- halogen exchange, benzyne, and the Wittig rearrangement.

? General Scheme
O R C R'(H) + X R"' CH R" + Ph3P R C R' (H) C R" R"'

? Features
? Mild reaction conditions; ? The position of the double bond is unambiguous.
HO 1) MeMgI 2) H + Me -H2O CH3 + CH2

O

CH2 Ph3P=CH2

? Representative Examples
Example 1

Example 2

Example 3

Example 4

? Mechanism [2 + 2] cycloaddition.

? Activity and stereoselectivity of Yild
Ph3P-CHR R = alkyl,EDG
Stability increase

Stereoselectivity Z(major)

R = alkenyl or alkynyl R = EWG

Z / E ( mixture) E(major)

? Influence of solvent on the selectivity
Ph3P-CH2CH3 + EtCHO PhCH=CHEt Z/E DMF + Li C6H6 + Li 96 / 4 0 / 100 + Ph3 PO

? Schl?sser modification: allows the preparation of trans vs. cis olefins.

Schl?sser Angew. Chem., Int. Ed. Eng. 1966, 5, 126.

? Stabilized Ylides

- Stabilized ylides are solid; stable to storage, not particularly sensitive to moisture, and can even be purified by chromatography.
- Because they are stabilized, they are much less reactive than alkyl ylides. They react well with aldehydes, but only slowly with ketones. - The first step, involving the addition to the aldehyde, is slow and reversible with stabilized ylides.

? Influence of solvent on the selectivity

? Wadsworth–Horner–Emmons Reaction

Horner Chem. Ber. 1958, 91, 61; 1959, 92, 2499.
Wadsworth, Emmons J. Am. Chem. Soc. 1961 , 83, 1733 . Reviews: Org. React. 1977, 25, 73–253.

Comprehensive Org. Syn., Vol. 1, 761.

? Preparation of Phosphonate Esters - Arbuzov Rearragement

Arbuzov J. Russ. Phys. Chem. Soc. 1906, 38, 687. - The same approach to the preparation of ?-ketophosphonates is not successful:

? Peterson Reaction

Reviews: Org. React. 1990, 38, 1.

Me3 Si

CH2 M +

C

O

C O

C SiMe3

+ Me3SiO -

Peterson reaction offers an alternative to Wittig procedure. They are more reactive and sterically less demanding than a Wittig reagent and the volatile byproduct (Me3SiOH/ Me3SiOSiMe3) is simpler to remove than Ph3PO. It does, however, require a second step to promote elimination of the ?-hydroxysilane.

- The elimination is stereospecific:
acid-promoted being anti and base-promoted being syn.

Hudrlik, Peterson J. Am. Chem. Soc. 1975, 97, 1464.

? Stabilized Peterson Reagents

- The stabilized Peterson reagents give predominantly the most stable trans olefins ( E)

- Additional examples:

4. The Tebbe Reaction and Related Titanium-stabilized Methylenations (Tebbe反应及与有关稳定化钛试剂的亚甲基化反应)

- Tolerates ketal and alkene derivatives.
Scope defined by Evans and Grubbs J. Am. Chem. Soc. 1980, 102, 3270. Extended to tertiary amides by Pine J. Org. Chem. 1985, 50, 1212.

For an analogous use of Cp2TiMe2: Petasis J. Am. Chem. Soc. 1990, 112, 6392.

6. Decarboxylation of ?-lactones (?-内酯的脱羧反应)
R R1 R R
1

R + CO2

CO O

140 ~ 160oC R2 R3

2

Synthesis of tri- or tetrasubsituted alkenes

R3

Example 1
H CH3 C6H5CH2 CO2H OH C6H5 C6H5SO2Cl Pyridine 0oC CH3 C6H5CH2 H CO O C6H5 C6H5CH2 ( > 99% E) C6H5 140 ~ 160oC CH3 H

Reformatsky Reaction

Note: No stilbene was formed

Example 2
O OH Me C Me CF2CO2H PhSO2Cl / Py CHCl3, 0 C
o

O Me C Me

C CF2 - CO2

Me C Me 87% CF2

Molbier W. R. et al. J. Org. Chem., 1995, 60, 5378

Example 3
CO2H OH

Me2NCH(OMe)2 DMF, 50 C
o

70%

Fehr C. et al. Tetrahedron Lett., 1992, 33, 2465

7. Oxidative decarboxylation of carboxylic acids ( 羧酸的氧化脱羧反应)
CO2 H CO2 H Pb(OAc)4 C 6H 6 Reflux

Sheldon, R. A., et al., Organic Reactions, 1972, 19, 279.
Example 1
CO2H

Pb(OAc)4 / O2 Py,

76%

CO2H

与 DiealAlder 反应结合, 是制备环状烯烃 的好方法。

Jahngen, B. G. E., J. Org. Chem., 1974, 39, 1650.

Example 2
CO2H

Pb(OAc)4 / Cu(OAc)2 . H2O C6H6, Reflux

77%

Example 3
CO2H Pb(OAc)4 / Cu(OAc)2 . H2 O Me + Py, C6 H6 Reflux 2.7 : 1

Tanzawa T. et al. Tetrahedron Lett., 1992, 33, 6783

8. Alkenes from arylsulphonylhydrazones (由芳基磺酰腙制备烯烃)
R R' O ArSO2NHNH2 R R' NNHSO2Ar R 1. 2 eq. BuLi 2. E+ E R'

Mechanism
R R' NNHSO2Ar BuLi R R' N N SO2Ar BuLi N N R R' SO2Ar

R - ArSO2H N N R' Li

R

R' Li

R E
+

R' E

Kolonko K., et al. J. Org. Chem., 1978, 43, 1404; Adlington R. M., et al. Acc. Chem. Res., 1983, 16, 55

Example 1
1. 2 eq. BuLi C6H5 NNHTos C6H14 - TMEDA 2. D2O C6H5 D 74%

Less substituted alkene Example 2
i-Pr NNHSO2 i-Pr C6H13 2 eq. BuLi C6H14 - TMEDA HO MeCHO C6H13 C6H13 H 2O C6H13 Li CO2 C6H13 H Pr-i

Me

CO2H

9. Fragmentation Reactions (裂解反应)

X

a

b R

O

H

Base R O

X = leaving group, e.g.: -OSO2C6H4CH3-p, -OSO2CH3 Example

100% stereospecific

10. Olefin Inversion Reactions (烯烃构型转换反应)
R' R R R'

? Deoxygenation of epoxides (with retention of geometry)

Other examples

11. Srereospecific synthesis of alkenes from 1,2-diols (由1,2-二醇立体选择性地合成烯烃)

Corey–Winter Olefin Synthesis

Corey J. Am. Chem. Soc. 1963, 85, 2677. Corey J. Am. Chem. Soc. 1965, 87, 934.

Eastwood Aust. J. Chem. 1964, 17, 1392. Eastwood Tetrahedron Lett. 1970, 5223.

Burgstahler, Boger Tetrahedron 1976, 32, 309.

12. [3,3]-Sigmatropic Rearrangements ? Claisen and Cope Rearrangement

Examples

Evans J. Am. Chem. Soc. 1975, 97, 4765.

Burgstahler J. Am. Chem. Soc. 1961, 83, 198.

Carnduff J. Chem. Soc., Chem. Commun. 1967, 606.

? Thio-Claisen Rearrangement

- An advantage of the thio-Claisen rearrangement is that the precursor can be deprotonated and alkylated.

Corey J. Am. Chem. Soc. 1970, 92, 5522. Yamamoto J. Am. Chem. Soc. 1973, 95, 2693 and 4446.

Block J. Am. Chem. Soc. 1985, 107, 6731.

?The Carroll Reaction

Carroll J. Chem. Soc. 1940, 704, 1266. Hartung J. Chem. Soc. 1941, 507. Cope J. Am. Chem. Soc. 1943, 65, 1992. Tanabe J. Am. Chem. Soc. 1980, 102, 862.

Chapter 4 Conversion of Functional Groups

1. Addition of Carbon-Carbon Double Bonds

H A A = H, OH, X, OCOR

Addition

X

X

Epoxidation
X OH

O
OH OH

OH

NRR'

2. Halogenation of Alcohols
? General Methods

R-OSO2R'

R

OH

R HX

X

Genaral reagents

PX3 SOCl2

? Development ? TCT/DMF Method

Org. Lett., 2002, 4(4), 553-555

TCT

2,4,6-trichloro[1,3,5]triazine

Table 1. Conversion of Aliphatic Alcohols into the Corresponding Alkyl Halides

a

For complete conversion of the alcohol. b The corresponding chloride is formed also.

Table 2. Conversion of Diols and Unsaturated and ?-amino Alcohols into the Corresponding Alkyl Halides

a

For complete conversion of the alcohol. b The corresponding chloride is formed also.

Mechanism

? Me3SiCl

OH

Me3SiCl DMSO r. t.

Cl

95%

该方法对苄醇、伯醇、烯丙醇、 叔醇,室温下反应迅速,收率高。

J. Org. Chem. 1995, 60, 2638

3. Formation of Amines
? General Methods
R N-Alkylation R R X OH OSO2Ar

R

NO 2

R
Reduction

R CN R CONR'2 RR'C NR"R'"

N R' R"

Rearragement

Hofmann 重排 Lossen 重排 Curtius 反应 Schmidt 反应

与氮烯有关的重排反应
R NH2 + Br2 OH
-

R O R

N Br

-Br-

O Hofmann R O Curtius Cl + NaN3

N + N N O

-N2

R

OH O Schmidt

+ HN3

H+

R O

N + N N

-N2

O

C

N R H2O -CO2

HNO3 -H2O R O Schmidt R NHOH R'CO H 2 O Lossen R O NH O R' OEt + N2H4 EtOH R O O -R'CO2H NHNH2

RNH2

? Synthesis primary amine ? Gabriel Synthesis
O NH O :B + RX 1) :B 2) H2NNH2 O H2NNH2 O RX NR . X O RNH2 + O NH NH

O N O

Harsh hydrolysis conditions
? Improvement Synthesis, 1990, 8, 735; 1995, 7, 756 Synlett, 1996, 2, 179; Synth. Commun., 1999, 29, 2685

? Development

Synthesis of Arylamines from amination of Aryl Halides

? Early Palladium-Catalyzed Amination

R Br + Bu3Sn "R N R'

[L2PdCl 2] L=p(o-C6H4Me)3 "R

R N R' + Bu3SnBr

M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927-928

该反应仅限于仲胺与电中性的卤代苯。

MeO2C H2N Br

N

CO2Me Me [Pd(PPh 3)4]

MeO2C

N

CO2Me Me

HN

D.L. Boger, et al., Trtrahedron Lett., 1984, 25, 3175 D.L. Boger, et al., J. Org. Chem. 1985, 50, 5782-5789; 5790-5793

要求等当量的有机钯催化剂。

J. Am. Chem. Soc., 1994, 116, 5969-5970 P. Patt, Hartig et. al.
L Pd Ar Br Br Pd L L R3SnNR2 ArNR2 + Pd0

L

Pd

L 3

ArBr

发现 Pd 可循环使用
从 1985 到 1994 近 10 年没有关于 Pd 催化胺化反应的报道。

存在的问题: 1)要将胺变成锡胺化物;
2)不适应于伯胺; 3)反应速度较慢; 4)催化剂用量较大。

? Initial Tin-free Amination of ArX

X Br + HNRR'

L2PdCl2 L-P(o-C6H4Me)3 Base

X NRR'

Hartwig and Buchwald, Angew. Chem. Int. Edu., 1995, 34, 1348-1350; Tetrahedron Lett. 1995, 36, 3609

J. Org. Chem. 1997, 62, 6066-6068

Room Temperature Catalytic Amination of Aryl Iodides
John P. Wolfe and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Table 2. Room Temperature Catalytic Amination of Aryl Iodides

Table 2. Continued

Chapter 5
Application of Organometallic Reagents in Organic Synthesis

非过渡金属有机试剂
八隅体电子构型 (s, p)

金属有机试剂

过渡金属有机试剂
十八隅体电子构型 (s, p, d
0-10

)
Sc, Y, La(镧系) 17种

稀土金属试剂
(s, p, d. f 1-14)

5.1 基本原理
5.1.1 非过渡金属试剂的特性
? 电负性
非金属 金 属 O S N Li X Cd Na K . . . . > C < C Mg Cu

? 反应活性
主族 Li-R < Na-R < K-R < Rb-R < Cs-R

副族 Cu-R > Ag-R > Au-R ; Zn-R > Cd-R > Hg-R 主副族比较 Li-R > Cu-R; Be-R > Zn-R; Mg-R >> Zn-R 同一周期 Li-R > Be-R > B-R; Na-R > Mg-R > Al-R;

? 反应性
Nu ?+ C
?C

?non-metal
?+ M

HO + CH3-I

CH3OH + I-

E+

CH3-I + Me-M

CH 3Me + M+ + I

-

? 特性总结 a. 含有 C-M 键 b. C-M键中 C为电负性的

c. C-M键中 的C原子常被亲核试剂进攻
? 金属有机试剂中常见的金属部分

Na, K, Li, Mg, Zn, Cu, Fe, Pd, Ni, Ti

5.1.2 金属试剂的制备通法
1) 卤代烃与金属反应

R-Br + 2Li

R-Li + LiBr

2)有机金属化合物与卤代烃的交换
R-X + R'-M Ph-Br + Bu-Li R-M + R'- X PhLi + BuBr

3)有机金属化合物与金属盐的交换
2R-Li + CdCl2 R2Cd + 2LiCl

M 的电正性 M 的电正性

C-M 的稳定性 C-M 的稳定性

4) 烃的金属化
RC C H + C2H5 MgBr RC ? + BuLi Li? + BuH C M gBr

5.1.3 结构与反应性

M % 离子性

K 51

Na 47 离子键

Li 43

Mg 35

Cd 15

极性共价键

反应性

降低

5.2 有机镁试剂(Grignard reagents)
通常表示为: RMgX, 以乙醚溶液使用

实际存在方式:

Br Mg R 单体

OEt2 OEt2

Et2O Mg R

Br Mg Br 二聚体

R

OEt2

5.2.1

制备
Et2O RMgX

R-X + Mg R: X:

烷基、芳基、 烯丙基、烯基、苄基 I > Br > Cl >> F

MeI

EtBr

? 通常用乙醚作溶剂,但制备芳基和烯基类G-试剂 时,要用THF作溶剂,以便提高温度,使反应进行 完全。

5.2.2 特殊的反应性
E MgX + E E 反常 正常

MgX MgX

Br O C R R' CH3 + Mg R R' OH

5.2.3 在合成上的应用
? 烷烃的制备

R-MgX + MeX

R-Me + MgX 2

Me2SO4 ArCH2MgCl n-C4H9OTs

ArCH2Me + MgCl(OSO2OMe)

ArCH2 C4H9-n + MgCl(OTs)

碳链非异构 化产物

? 醇的制备
OH RCHO R R R' "R R "R "R R" 伯或仲醇

RCOR' R"MgX RCO2R'

OH

叔醇

OH

O

R"CH2CH2OH

O + RMgX

MeMgX O MgX

Me

OH

H O 1) RMgX 2) H + O

R OH R + OH 1,2-addition R O 1,4-addition

选择性 差

? 醛的制备
RM gX C2H5O C2H5O C H HC OC2H5 + OC2H5
RMgX

OC2H5 RCH OC2H5

H / H 2O

+

RCH O

OC2H5

CH3(CH2) 4MgBr + HC(OC2H5) 3

H / H2O

+

CH3(CH2) 4CH 45%~50%

O

增加一个碳原子

R R C O + BrMgC C OEt

1) 加成 2) H
+

R R

OH C C

C OEt

[H]

R R

OH H+ / H2 O C CH CH OEt

R R

OH C CH

CH

OH

R R

OH C CH2 CHO

R C R CH CHO

BrMgC O OCH3

C

OEt

CHO OCH3

? 酮的制备 a.
RMgX + R' H + R' R C N H2O -NH3 R' R C N MgX R' R

C NH

C O

b.
O RMgX + R' + C NR"2 R' R O

MgX

C NR"2

H

R' R

C O +

MgX+ + R"2NH

c.
-78oC PhCOCl + MgCl H+ / H2O

COPh

CH3(CH2)5MgBr + n-C3H7COCl -30oC H+ / H2O

CH3(CH2)5COC3H7-n

5.3 有机锂试剂(Organolithium reagents)
活性: RNa > RLi > RMgX

5.3.1 制备
R-Br + 2Li
Ph-Br + Bu-Li

R-Li + LiBr
PhLi + BuBr

- configurationally stable - retention of configuration

5.3.2 反应
? 能克服位阻的影响

+

MgX OLi
H+

O OH

+

Li

? 与 ?, ?-不饱和酮主要发生1,2-加成

Ph PhMgBr Ph O Ph Ph PhLi Ph

O Ph 1,4- 主要产物

OH Ph 1,2- 主要产物

Ph

? 与羧酸、CO2反应生成酮
1) RMgBr 2) H + CO2 1) 2) H
O RLi + R' C OLi

RCO2H

2 RLi
+

RCOR

OLi R' C R OLi

H / H2O

+

O R C R'

O COOH
1. 4eq. CH3Li 2. TMS?Cl 3. H+ / H2O

C

CH3 92%

5.4 有机锌试剂(Organozine reagents)
? Reformatsky 反应及扩展
PhCH O + BrCH2COOC2H5
1. Zn 2. H+ / H2O

Ph

CH OH

CH2COOC2H5

O
Zn

O + PhCH = O
Et2AlCl

Br

CH OH

Ph

O R CH Br C OC2H5 + RCN
Zn

R C C2H5OOC C

R' NH2

H /H2O

+

R CH

O C R'

C2H5OOC

―一锅煮”制备 ?, ?- 不饱和羰基化合物, Zn催化
RCHO + BrCH CO2CH3 + n-Bu3P(As) 2 Zn RCH CHCO2CH3

RCHO + BrCH CONRR' + n-Bu3P Zn 2

RCH

CHCONRR'

RCHO + BrCH CN + n-Bu P 2 3

Zn

RCH CHCN

将三步的Wittig反应压缩为“一锅”法完成。
沈延昌, 金属有机化合物的化学反应, 化学工业出版社,2000.7. P 60-78

O C2H5O C (CH2) n I

Zn

Cu

O C2H5O R C Cl O O R C (CH2) n COOC2H5 R CH (CH2) n COOC2H5 RCH CH CH2 (CH2) n C (CH2)nZnI RCHO TMSCl RCH CH CH2 X O C OEt

OTMS

? Lombardo’s试剂 (Zn + CH2Cl2 + TiCl4)

O Ti R C R R

O C CH2

Ti R Zn ? R C CH2 R

Zn

CH2

Zn C4H9 H C CH3O C CH(CH3) 2

C4H9COOCH3 + (CH3)2CHCHBr 2

Zn TiCl 4

J. Am. Chem. Soc. 2003, 125, 338-339

A Direct Catalytic Asymmetric Mannich-type Reaction to syn-Amino Alcohols
Barry M. Trost* and Lamont R. Terrell
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080

Scheme 1. Generation of Dinuclear Zinc Catalysts

Table 1. Additions to Glyoxalate Imines

Table 2. Additions to Aldimines

5.5 有机镉试剂(Organocadmium reagents) ? 制备
2R-Li + CdCl2 R2Cd + 2LiCl

? 反应活性远低于RMgX 和RLi ? 反应
2 RCOCl + R'2Cd
R'MgX R'Li R'2Cd

RCOR' + CdCl2

RCOR' RCOR' RCOR'

只适用于制备 位阻较大的酮

RCOCl

5.6 有机铜化合物(Organocopper compounds)

RCu
5.6.1 制备
RLi + CuI 2RLi + CuI

R2CuLi

RCu + LiI R2CuLi + LiI
R R Cu -

H

H

+

R2CuLi

Li+

5.6.2 反应
? 与 ?, ? -不饱和羰基化合物反应

均为1,4加成产 物
O 98% H3C CH3

O CH3

+ (CH3)2CuLi

O (CH3) 6COOCH3 + (CH2=CH) 2CuLi

O (CH2) 6COOCH3

CH

CH2

66%

? 与卤化物反应
RX + R'2CuLi R R'

C10H21Br + Bu2CuLi

C14H30

80%

Br

+

Bu2CuLi

Bu

80%

H 3C H

H Cl

Li

H 3C H

H Li

CuI, - 78 oC H3C n-C8H17I H

H C8H 17-n 90 -93%

? 与环氧化物反应
O + (CH3)2CuLi CH3 CH2 CH3CH2 CH OH CH2CH3 88%

CH3 O

CH3 1) R2CuLi 2) H+ OH R

从位阻较小的一侧,取代基较少的碳原子上进攻。

5.7 有机钯化合物 (Organopalladium compounds)

形成过渡 金属络合 物中间体

在配位体 上进行化 学反应

去络合 反应

过渡金属参与有机反应的三个阶段

[(C2H4)PdCl] 2

1938

化学计量到催化循环

1956,Smidt, German, Eacker Company

[M2PdCl 4]4, M=Li, Na, K Pd
2+

PdCl 2

[(PhCN) 2PdCl 2] [Pd(OCOCH 3)2] [Pd(OCOCF 3)2]

Pd

0

[Pd(PPh)4] [Pd(PPh)4] [PdL4]

? ? 络合物
CH2 = CH2 + PdCl2 + CH2 Pd ++

Pd

CH2 Nu ?

CH2 [H] Nu

CH2

Pd ++ -Pd -H+
o

CH2 Nu

CH3

CH Nu

CH2

Wacker 反应
PdCl 2

C8H17CH

CH2 + H2O

C8H17 O

CH3

CuCl 2 O2

CH3 CH2 CH CH2 C CH O

CuCl 2 PdCl 2 H2O DMF O2

CH3 CH3 C O CH2 C CH O

CH3

CH3 78%

? ?3-烯丙络合物 制备
Pd + CH2 CH CH2Br ? ?3 C3H5)PdBr 2

黄 色 固 体 dp 135℃

RCH2

CH

CH2 PdCl2 R H

H H H

RCH O

CH C O

CH2

Pd 0

CH3

Pd

++

反应
H Nu ? R CH2 Pd
++

R H H

H

H Nu ? ?Pd0 ? ?H+ R CH CH CH2Nu

Pd ++

O O CH3OOC C CH3 Pd(PPh 3) 4
NaCH(COOC2H5)2

CH(COOC2H5) 2 CH3OOC 57%

? Pd络合物的氧化加成反应(Heck Reaction)
PPh3 Pd(OAc) 2 R R'
R'

H R"

RX

+ R'

R"

PdX
R'' R' R''

RPdX

R H Syn加 成 R' H

R''

RPdX

pdX H R"
?HPdx Syn清除

H H R R'

R''

R

R'

Br

+ CH2

CH

COOCH3 (PPh3)2 Pd(OAc)2
R3N

CH

CHCOOCH3

85%

I + CH2 Br CH COOH
Pd(OAc)2

CH

CH

COOH

Br 82%

Br O N CH3
Pd(OAc2, PPh3 ) Et3N

N CH3

O

85%

Heck Reaction (Review)
1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518; 2. Heck, R. F. Acc. Chem. Res. 1979, 12, 146; 3. R. F. Heck, Organic Reactions, 1982, 27, 345;

4. A. de. Meijere and F. E. Meyer, Angew. Chem. Int. Ed. Engl., 1994, 33, 2379;
5. W. Cabri and I. Candiani, Acc. Chem. Res., 1995, 28, 2; 6. G. T. Grisp, Chem. Soc. Rev., 1998, 27, 427 7. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 341.

J. AM. CHEM. SOC. 2003, 125, 1484-1485

Oxidative Heck-Type Reaction Involving Cleavage of a Carbon-Phosphorus Bond of Arylphosphonic Acids
Atsushi Inoue, Hiroshi Shinokubo,* and Koichiro Oshima* Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan

Table 2. Oxidative Heck-Type Reaction of Arylphosphonic Acids

? 偶联反应
H C R C Pd
++

H + R'M X

H C R C

H Pd R'

H C R C

H + Pd0 R'

催化剂: Pd(PPh3)4
H C C 6H 13 C I H + H Br M g C C H H P d ( P P h 3) 4 H C C 6H 13 C CH C H2 H

Cu +

RC

CH

RC

CCu

R 'P dX

RC

C R' + Pd 0

Suzuki Reaction
R X + R1 B(R2)2 L2Pd(0) NaOR
R Pd L X OR3 R1 B(R2)2 + NaOR3 R1 B(R2)2 L
3

R

R'

R

X

+

L2Pd(0)

氧化加成

R Pd L

L + X R1

OR3 B(R2)2 -

金属转移化 异构化

R Pd L

L + R
1

R 3O

B(R2)2

还原消除 R R1 + L2Pd(0)

Suzuki Reaction
1. N. Miyaura and A. Suzuki. Chem. Rev. 1995, 95, 2457 2. A. Suzuki, Puer Appl. Chem., 1994, 66, 213; 3. N. Miyaura and A. Suzuki, Org.Syn., Coll.Vol. VIII, 1993, 532; 4. B.E. Huff, T. M. Koenig et al., Org. Syn., 1996, 75, 53; 5. F.E. Goodson, T.L. Wallow and B.M. Novak, Org. Syn. 1996, 75, 61; 6. F.S. Ruel, M.P. Braun and C.R. Johnson, Org. Syn., 1996, 75, 69 7. Miyaura, N. Top. Curr. Chem. 2002, 219, 11-59. 8. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 2. 9. J. Hassan,. M. Se?vignon; C. Gozzi; E. Schulz; and M. Lemaire Chem. Rev. 2002, 102, 1359-1469

J. Am. Chem. Soc. 2002, 124, 13662-13663

Boronic Acids: New Coupling Partners in RoomTemperature Suzuki Reactions of Alkyl Bromides. Crystallographic Characterization of an OxidativeAddition Adduct Generated under Remarkably Mild Conditions
Jan H. Kirchhoff, Matthew R. Netherton, Ivory D. Hills,1 and Gregory C. Fu*

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Table 1. Suzuki Cross-Coupling of n-OctBr with PhB(OH)2 (5% Pd(OAc)2, 10% ligand, rt): Effect of Additive, Solvent, and Ligand

n-BuBr + PhB(OH)2

n-Bu-Ph

Table 2. Pd/P( t-Bu)2Me-Catalyzed Suzuki Cross-Couplings of Alkyl Bromides with Boronic Acids

Table 1. Heck Coupling Reactions Catalyzed by 4

Table 2. Suzuki Coupling Reactions Catalyzed by Complex 4b

Table 3. Sonogashira Coupling Reactions Catalyzed by 4b

? CO插入反应

C2H5 C H C

C2H5 + CO I

PdI2(PPh 3)2 n-BuOH

C2H5 C H C

C2H5 COOC4H9

CH3 C I C

H CH OH CH3
Pd(PPh 3)2Cl2 CO

CH3 CH3 O O 99%

5.8 有机镍化合物 ? ?3-烯丙基镍络合物的制备
Br

2 CH2=CHCH2Br + 2 Ni(CO)4

Ni Br

Ni

Br R Ni Br Ni R

R = H, CH3, CO2C2H5, etc.

? ?3-烯丙基镍络合物偶联反应
Br

R 2 2 R' CH2 C CH2

2R'X +

R

Ni

R’ 4-羟基环己基

R CH3

收率 88%

C6H5

CH3

98%

Br Br Ni 2

Br

OAc

Br ? ? ?

Cl [Ni(PPh3)2COD] O O O O

Br [NiClL2]/ MeMgBr N Me N Me

CH2Br

O O Ni(CO)4

O O

CH2Br

2 NC

Ni(COD) 2 Br NC CN

1,5-cyclooctadiene

? 镍络合物催化格氏试剂的反应
O R C OH + R'MgX O NiCl2(dppe)

60-75%
R R' dppe = Ph 2PCH2CH2PPh2

E. Wenkert, et. al., J. Chem. Soc., Chem. Commun., 617(1984)
P * Cl2Ni OPh + EtMgBr P * * Et yield 85% e.e. % 97.7%

G. Consiglio, et. al., J. Chem. Soc., Chem. Commun., 112(1983)

Chapter 6
Diels-Alder Reaction and Development

Discovery
? Wieland ( Ber. 1906, 39, 1492) described the 1:1 dimerization of conjugated dienes in what was probably the first report of a Diels–Alder reaction. ?Albrecht (Thiele) Reaction: Ann. 1906, 348, 31.

? Staudinger Structure: Die Ketene, Stuttgart 1912, 59.

? Diels and Alder Ann. 1928, 460, 98. ? In fact, von Euler had correctly, but tentatively, identified the 2:1 adduct of isoprene with p-benzoquinone before Diels and Alder's work. von Euler, Josephson Ber. 1920, 53, 822.

Diastereoselectivity
a. cis Principle:
? Geometry of dienophile and diene are maintained in the [4 + 2] cycloadduct.

b. Alder's Endo Rule: Stereoselective e.g. Endo product and endo transition state predominate even though exo products are usually more stable; endo is the kinetic product.

Result: Both cis rule and endo rule

Diels–Alder reaction very useful, diastereoselective

c. Factors influencing endo selectivity of the Diels–Alder reaction ? Endo transition state is favored by stabilizing secondary orbital interactions. ? Endo selectivity often increases with the use of Lewis acid catalysis. ? Endo selectivity often increases with increase in pressure of reaction. ? Endo selectivity also increases with decreases in temperature at which the reaction is conducted.

Small Organic Molecular Enantioselective Catalysts
R + 20mol % A-HCl R O 23 C X O Me N N H A Me Me yiled: 72-90%; % ee: 83-96%
o

CHO

X

Ph

David, W. C. MacMillan, J. Am. Chem. Soc. 2000, 122(17), 4243-4244

X +

O

R' 20mol % A-HCl

X COR' Is OK? R

R

O R1 O + Me Et

Me N R2 HClO 4 3 R Me O

N H 20mol %
o

H2O, 0 C Et

catalyst A: yield 20%; endo:exo = 7:1; % ee = 0 The best catalyst 5: yield: 89%; endo:exo = 25:1; % ee = 90 Catalyst 5: R1 = Bn, R2 = 5-Me-furyl, R3 = H

O 20mol % Cat. 5 + R
1

R

2

20mol % HC l O 4 H2O, 0oC

R1 R
2

O

Et + O 20mol % Cat. 5 20mol % HC l O 4 o EtOH, -30 C X yields: 78-90%; endo:exo > 100:1; % ee = 85-98

COEt

X

Joel F. Austin and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124(11), 2458-2430

Chem. Rev. 1996, 96, 167-176

Tandem Diels-Alder Cycloadditions in Organic Synthesis
Jeffrey D. Winkler Department of Chemistry, The University of Pennsylvania, Philadelphia, Pennsylvania 19104

Reactions of Bicyclic Bis-Dienes

Visnick, M.; Battiste, M. J. Chem. Soc., Chem. Commun. 1985, 1621.

Acetylenic Bis-Dienophiles

Goldberg, D.; Hansen, J.; Giguere, R. Tetrahedron Lett. 1993, 8003. Nahm, S.; Weinreb, S. Tetrahedron Lett. 1981, 3815.

Exocyclic Bis-Dienes

Hosomi, A.; Masunari, T.; Tominaga, Y.; Yanagi, T.; Hojo, M. Tetrahedron Lett. 1990, 6201.

Masked Bis-Dienes

Bluestone, H.; Bimber, R.; Berkey, R.; Mandel Z. J. Org. Chem. 1961, 26, 346.

Swarbrick, T.; Marko, I. Kennard, L. Tetrahedron Lett. 1991, 2549. Marko, I.; Seres, P.; Swarbrick, T.; Staton, I.; Adams, H. Tetrahedron Lett. 1992, 5649.

Reddy, G.; Bhatt, M. Tetrahedron Lett. 1980, 3627.

Chapter 7

Oxidation Reactions

氧化反应的概念
广义的概念 碳原子周围电子云密度的降低,即碳原子氧 化数(氧化态,氧化值)升高的反应。 狭义的概念

加氧反应和/或脱氢反应。

氧化反应的分类
1. 碳原子上的氢被吸电子的基团或原子取代
CH2 R CO2H

HNO3

NO2

RCH3

Cl2

RCH2Cl

2. 碳碳相联接转变成与吸电子基团或原子相联接
OH O OH 2 HCHO

Br

Br

3. 脱氢
Ph Ph + 2H2

+

2H2

4. 功能团的氧化
RCH2OH RCHO RCO2H

C6H5NO

C6 H5NO2

理想的氧化反应
? 选择性高 ? 反应条件温和 ? 环境友好 ? 原料便宜易得

? Epoxidation reactions: --------- Oxidation of Carbon-Carbon Double Bonds
Comprehensive Org. Syn., Vol. 1, 819; Vol. 7, 357, 390.

Peracid Oxidation

O R O OH + C C R

O OH +

O

1. Peracid Reactivity:

CO2H

Rate increases: R = CH3 < C6H5 < m-ClC6H4 < H < p-O2NC6H4 < pKa of acid (RCO2H): 4.8 4.2 3.9 3.8 3.4 2.9

<CF3 0

The lower the pKa, the greater the reactivity (i.e., the better the leaving group)

2. Mechanism:

O R R R R R1C O O H R R

O H O O R R C R1 R R O R R

过氧酸对双键发生亲电进攻,形成环氧化合物。

3. Stereochemistry: a. Stereochemistry of olefin is maintained: diastereospecific. b. Reaction rate is insensitive to solvent polarity concerted mechanism without intermediacy of ionic intermediates. c. Less hindered face of olefin is epoxidized.
R R m-CPBA R R O + O R = H 20 min. 25 oC R = CH3 24 h, 25 oC, 99% <10% 1% 90% R R

4. Chemoselectivity: --Electrophilic reagent: most nucleophilic C=C reacts fastest.

> RO R

> EWG

>

>

>

>

>

--Examples:
O m-CPBA
-10 C, 1h
o

cis : trans 1:1

C6H5CO3H CHCl3, 10 min. 0 C.
o

O
Concave face hindered toward peracid attack H

HO2C

H

O
C6H5CO3H C6H6-dioxane 25 C, 24h
o

HO2C O

H

O

CO2H OH O H

H

OH

H 80%

OH

H Convex face open to peracid attack

5. Diastereoselectivity
? Endocyclic Olefins
Destabilizing steric interaction between reagent and axial Me Me H Me H Attack principally from this face

( )

? Exocyclic Olefins
more hindered face Me Me Me less hindered face --Solvent dependent

( )
RCO3H Me

Me O Me less stable product 75% 80% 83% + Me

Me

O

Me

CCl4 C6H6 CH2Cl2 or CHCl3

25% 20% 17%

Henbest, J. Chem. Soc., Chem. Commun., 1967, 1085.

----The effective size of the reagent increases with increasing solvent polarity, i.e. the solvation shell of the reagent increases in size

---Small reagent preference: axial attack and 1,3-diaxial interactions vary with size of the reagent.
H H H
RCO3H

H

O +

H

O H

H

H

H H 41

H

H :

H 59

H

H

---Large reagent preference: equatorial attack and 1,2interactions (torsional strain) are relatively invariant with the size of the reagent.
Carlson, J. Org. Chem., 1967, 32, 1363.

? Allylic Alcohols (endocyclic)

Henbest J. Chem. Soc., 1957, 1958; Proc.Chem. Soc, 1963, 159.
O OR m-CPBA 20 oC C6H6 5 oC C 6H 6 O OR + 43% 9% 57% 91% 38% yield 86% yield

OR

R = COCH3 R=H

O OH m-CPBA

O OH + Bu-t 4% Bu-t 96%

OH

Bu-t
Prefers equatorial position, lockoing conformation of substrate.

R H O
120
o

O O O H

R

---Metal-catalyzed epoxidations of allylic alcohols

Sharpless Aldrichimica Acta 1979, 12, 63.

? Allylic Alcohols (exocyclic)

Vedejs and Dent., J.Am.Chem. Soc., 1989, 111, 6861.

? Acyclic Allylic Alcohols Generalizations:
Eclipsed Conformations in m-CPBA Epoxidation

Bisected Conformations in Metal-Catalyzed Epoxidation

Examples:
R1 threo OH R = Me
1

erythro 40 80

m-CPBA VO(acac)2, BuOOH
t-

60 20

H vs. alkyl eclipsing interaction with double bond has little to no effect on selectivity. H eclipsing interaction slightly more stable.

HO H R
1

H H H threo

R1 = Et

m-CPBA VO(acac)2, t-BuOOH

61 20

39 80 H H OMet erythro R1 H H

R1 = i-Pr

m-CPBA VO(acac)2, t-BuOOH

58 15

42 85

H, H eclipsing in erythro T. s. favored over H, alkyl eclipsing in threo T. S.

(continued)

R2

R1 threo OH erythro 55 95
Erythro slightly favored due to Me, Me gauche interaction in threo T. S.

H Me HO

Me H H erythro Me H

R , R = Me

1

2

m-CPBA VO(acac)2, BuOOH
t-

45 5

R1 = Me R2 = n-Bu

m-CPBA VO(acac)2, t-BuOOH

41 2

59 98

H, Bu eclipsing in erythro T. s. favored over Me, Bu eclipsing in threo T. S.

Bu

H

H OMet erythro

(continued)

? Homoallylic Alcohols (高烯丙系)
H OH Ph Me Me VO(On-Pr)3
t-

L O H OTBDPS V L tO Bu O Me OH Ph Me O Me OTBDPS

BuOOH

Ph Me

CH2Cl2, 95% OTBDPS

--Alternative chair has two axial substituents. --Intermolecular oxygen delivery occurs through most stable chair-like transition state.

(continued)
VS. major OAc Ph Me Me
m-CPBA o CH2Cl2, 25 C 94%

Me OTBPS

Me Ph H OAc

OAc Ph Me 5:1

O Me OTBDPS

OTBDPS

) (
minor

--H-Eclipsed conformation. --Epoxidation from least hindered face; --Not a directed epoxidation! --Diadtereoselectivity still good and through H-eclipsed conformation.

Schreibe, Tetrahedron Lett. 1990, 31, 31 Hanessian, J. Am Chem Soc, 1990, 112, 5276.

? Other Directed Epoxidations
-- Studies suggest axial –NHCBZ delivers syn epoxide while equatorial does not.
R m-CPBA
CH2Cl2, 25 C
o

R O NHCBZ 100 100 100 100 0 0 0 0 0 0 + O

R NHCBZ

NHCBZ R = NHCBZ 86% = CH2OH 83% = CH2OAc 72% = CO2Me 59% = CH2OTBDPS 54%

Mohamadi Tetrahedron Lett. 1989, 30, 1309.

6. Scope and Limitations
Peracid + O

a. Olefin geometry is maintained. b. Reaction is diastereospecific: the stereochemistry of the reactant and product bear a definite relationship to one another. c. Reaction can be buffered to prevent epoxide opening.

d. At higher temperatures, a free radical scavenger may be used to avoid peracid decomposition. e. Common Side Reactions: ? Baeyer-Villiger Reactions of Ketones (and aldehydes)
O m-CPBA O O not O O

? Oxidation of amines

N

m-CPBA

+

N

O-

--Nitrogen must be protected (e.g. as amide) or another reagent selected.
? Imine oxidation
N R m-CPBA O N R

? Sulfur oxidation
R S R m-CPBA R S O R + R S O O R

7. Epoxidation of Electron-Deficient Olefins
a. ?, ?-unsaturated esters: can choose a strong peracid or vigorous reaction conditions.
Me CO2CH3
CF3CO3H Na2HPO4 CH2Cl2, reflux

Me O CO2CH3 84%

Emmons, J. Am.Chem.Soc., 1955, 77, 89.

Ph

Ph
m-CPBA Na2HPO4 CO2CH3 CH2Cl2, reflux

O

CO2CH3

MacPeek, J. Am. Chem. Soc. 47% 1959, 81, 680.

b. ?, ?-unsaturated ketone: Baeyer-Villiger competes with epoxidation
O R Epioxidation R1 Baeyer-Villiger Reaction

Solution: different conditions (reagents) are neede.

? Additional Methods for Epoxidation of Olefins
1. H2O2, NaOH
O
H2O2, NaOH

OH O O

O O

70%

--The following reaction is diastereoselective (not diastereospecific)
Me Me O
H2O2, NaOH

Me H

Me CO2CH3

H2O2, NaOH

Me

CO2CH3 Me

CO2CH3

The reaction occurs via a reversible process:
Me Me CO2CH3 Me H H O O Me Me OCH3 OMe CO2CH3

Similarly:
tBuOOH/Triton

B Payne J. Org. Chem., 1961, 26, 651. Ph3COOH/R4NOH Corey J. Am. Chem. Soc. 1988, 110, 649. tBuOOH/nBuLi Cegg Tetrahedron, 1988, 29, 48889.

2. Peroxyimidate
H2O2

NH R O O H O + R

O NH

RCN

--This reagent permits the use of neutral reaction conditions. Unlike m-CPBA, the reagent behaves as a large reagent and thus aproaches from the equatorial face of an exocyclic double bond.

H
Carlson, J. Org. Chem., 1967, 32, 1363.(m-CPBA & PhCN/H2O2)

H

) (
H

m-CPBA small reagent, but the interaction will increase with size of the reagent

Vedejs, J. Am. Chem. Soc., 1989, 111, 6861.(m-CPBA)

H

) (

PhCN/H2O2 large reagent, but the interaction will not vary with size, predominately equatorial attack.

--Analogous Reagent:
Ph N=C=O + H2O2 H N Ph O O O H
Christl Angew.Chem., Int. Ed. Eng., 1980, 19, 458.

3. Sulfur Ylides

--This is the result of kinetic control: reaction gives the thermodynamically less stable epoxide product.
H S
+

) (

H Bu
-t

Bu-t O 13% Bu-t 87%

O- Equatorial Delivery Bu O
-t

1,2-interaction disfavored

O

-

Bu-t S+

) HH (

O

Axial Delivery 1,3-interaction favored over 1,2

Corey, Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353.
O Me S+ CH277%

Bu-t O

Me

O 0 O S+ CH2-

Bu

-t

Bu-t + O

Me Me

O S+ Me I-

100 thermodynamic product Dimethoxo sulfonium methylide Small reagent that prefers axial delivery

NaH, THF reflux

Me Me

O S
equatorial attack
+

H H Bu OO H S+ H
-t

Bu-t
rapidly goes on to product

O 100%
-

Bu-t O

Bu-t
fails to go on to product

O H S+

Bu-t H

axial attack predominant

O

) (

backside attack not possible due to destabilizing 1,3-interactions

Initial reaction is reversible and is not capable of generating the axial delivery product because of the destabilizing 1, 3- interactions in the transition state required for epoxide closure.

Summary of Exocyclic Epoxide Formation

O

or X X=O X= CH2 S m-CPBA O X=O X= CH2 S+ CH2NH R O

O axial attack X X

equatorial attack

X X

O H

Sulfur yliedes deliver "CH2" Peracides deliver "O"

4. Dimethyl Dioxirane (DMDO)
A mild neutral reagent
Murray J.Am. Chem Soc, 1986,108,2470.
DMDO

Acc.Chem. Res., 1989, 22,205

O

O

acetone, 96%

O

O

O

Adam Tetrahadron Lett., 1989, 30,4223. O O CF3 CF3

O O

O

Curci Tetrahedron Lett.,1989, 30, 257

O
Boyd Tetrahedron Lett., 1989, 30, 123.

O . O
Crandall J. Org. Chem.Soc., 1989, 111, 6661. Tetrahedron Lett., 1988, 29, 4791. BnO BnO OBn O BnO BnO OBn O

O

Dnishefsky J. Am. Chem.Soc., 1989, 111, 6661.

R3SiO

R3SiO

O

O OSiR3

Stable and characterizable Danishefsky, J. Org. Chem, 1989, 54, 4249.

5. Summary of Other Methods of Epoxide Formation a. Cyclization of Halohydrins
HO + X 2 + H 2O X
+X tBu tBu

O

X+

axial
H2O CH2X
tBu

equatorial
H2O OH
t+ Bu

O CH2X
tBu

O
tBu

NXS/H2O

tBu

OH

+
major

minor

NCS-H2O NBS-H2O NIS-H2O

90 82 55

: : :

10 18 45

90 31

: vs : For m-CPBA complementary stereochemistry

10 69

Increased reagent size yields increased equatorial approach The electrophilic reagents behave as small reagents and approach from the axial direction

b. Cyclization of 1,2-diols

R OH OH

TsCl

R OTs OH

R O

--Primary alcohol > secondary alcohol for tosylation reacton

c. Epoxides from Carbonyl compounds
Cl 1). O + Li R R1 2). O O + S O O R 3). H O + Cl + S CH2 O X X
O

O

R R1

CH2 O

R

O O Darzen's Condensation

R= OR,

N R

O

Generalized by Darzen through years 1904~1937. Asymmetric variants / Evans Chiral Oxazolidinone Lantos J. Am. Chem. Soc., 1986, 108, 4595.

? Catalytic Asymmetric Epoxidation
1. Sharpless Catalytic Asymmetric Epoxidation (AE Reaction)
Key reference: Asymmetric Synthesis: Vol. 5, Morrison J. D. Ed. Chapter 7 and 8 Reviews: Katsuki, Martin Org. React., 1996, 48, 1. Comprehensive Org. Syn., Vol. 7, 389~436. Sharpless J. Am.Chem. Soc., 1980, 102, 5974; 1981, 103, 6237; 1984, 106, 6430; 1987, 109, 1279, 5765; 1991, 113, 106, 113; 1987,109,1279

(1) The enantiofacial selectivity of the reaction is general and dependable for assignments.
(S,S)-D-(-)-tartrate "O" R2 R1 R3 OH
t-

非天然

BuOOH, Ti(O Pr)4
CH2Cl2, -20 C
o

i

R2 O R3

R1 OH

DET or DIPT 4 A molecular sieves 70~90%

anhydrous >90% e.e.

"O" 天然 (R,R)-L-(+)-tartrate

(2). Selectivity is catalyst depent: Ti(OiPr)4 Al(OtBu)3 95% e.e. Zr(OiPr)4 5% e.e. Hf(OiPr)4 10% e.e. 3% e.e.

MoO2(acac)2
VO(OiPr)3 Sn(OiPr)4

15% e.e. Nb(OEt)3
17% e.e. Ta(OiPr)5 NR

5% e.e.
39% e.e.

(3). Sharpless Asymmetric Epoxidiation

the best known and practical asymmetric reaction
H E HO RO2C OH RO CO2R RO O Ti O RO O
t-

H

O Ti O Bu E O O R' E = CO2R

E

O

C2 symmetry

--Match of Ti/Tartrate such that a single complex dominates the chemistry. --Ligand acceleration of reaction. --Steric and stereoelectronic feactures of reaction control enantioselectivity

Epoxidation with Titanium-Tartrate Catalysts Scope
e.e. Unsubstituted (R1=R2=R3=H) trans-disubstituted (R1=R3=H) R2=CH3 R2=n-C10H21 R2=(CH3)2CH=CH2 R2=Me3Si R = Bu R2=Ar R2=CH2OBn R 2=
O O 2 t-

R2 R3

R1 OH

yield 15% 45% 79% 80% 60% 0~90% 85% 78~85%

95% >95% >95% >95% >95% >95% ~95% 98% >95%
O O O

R 2= R=
2

BnO

>95% >99%

70% 76% 70% 70~88%

BnO O

R=
BnO

2

>99%
Ph O O BnO OSiEt3 R

R 2=

>93%

(continued)

R2 R3

R1 OH

e.e. Cis-disubstituted (R2=R3=H) R1=n-C10H21 R1=CH2Ph R1=CH2OPh R 1= 1,1-disubstituted (R1=R2=H)
O O

yield 82% 83% 84% 55%

90% 91% 96% 96%

R3=-Cyclohexyl R3=n-C14H29 R3=t-Bu

>95% >95% 85%

82% 51%

(continued)
R2 R3

R1 OH
e.e. yield 81% 79% 70% 92%

trans-1,1,2-trisubstituted (R1=H)

R3=R2=Ph R3=Me, R2=Et R3=Me, R2= AcO R3=Me, R2=
O

>95% >95% >95% >95%
O

Cis-1,1,2-trisubstituted (R2=H) 1,2,2-trisubstituted (R3=H)

R3=CH3, R1=Bn R2=(CH2)2CH=C(CH3)2, R1=CH3 R2=CH3, R1=(CH2)2CH=C(CH3)2

91% >95% 94% 94% 94%

90% 77% 79% 90% 90%

tetrasubstituted

R3=CH3, R2=Ph, R1=Bn
OH

(4). Kinetic Resolution:

Sharpless, J. Am.Chem.Soc.,1981, 103, 6237 Pure Appl. Chem., 1983, 55, 589.

-- Sharpless epoxidation product is different from the directed oxidation of allylic alcohols by peracids (m-CPBA)

(5). Payne Rearrangement

Payne J.Org. Chem., 1962, 27, 3819.

Base-catalyzed (NaOH, aq.) migration of ?,?-epoxy alcohol.

? In general, the more substituted epoxide is favored as the reaction product. ? However, steric factors and relative alcohol acidities (1° > 2° > 3°) are additional factors which determine the ultimate composition of the equilibrium mixture.

? The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH).

O ROH2C H

OH H CH2OH ROH2C O PhSH ROH2C

OH SPh OH

2. Jacobsen Epoxidation
--Unactivated alkenes

H N Mn
t-Bu

H N O
t-

O Bu-t

Cl

Bu-t Bu

Jacobsens J. Am.Chem., 1991, 113, 7063.

Example:

Boger, Boyce Synlett 1997, 515.

3. Chiral Dioxiranes

O O
O

DMDO

O O H O catalytic amounts O

O O

oxone
CH3CN H O

O

O

O
O

O Chiral Dioxirane

Shi, J.Am. Chem Soc, 1996, 118, 9806 J. Am.Chem. Soc., 1997, 119, 11224. J. Org. Chem., 1997, 62, 2328.

--Examples of trans and trisubstituted olefins
Ph
Shi's Cat. (pH 10, K2CO3)

Ph H O C 3H 7 H
Ph

H Ph
73% yield >95% ee

Ph

C 3H 7
Ph

OTBS

Shi's Cat. (pH 10, K2CO3)

H O O 69% yield 91% ee. OTBS 80% yield 93% ee.

Shi's Cat. (pH 10, K2CO3)

---pH 10 (K2CO3, KHCO3) sppresses Baeyer-Villiger reaction of Ketone precursor.

---C2 symmetric Chiral Ketone

(过硫酸氢钾制剂)

Yang J. Am. Chem. Soc. 1996, 118, 11311; 1998, 120, 5943.

Polymer Supported Poly Amino Acids

Itsuno J. Org. Chem. 1990, 55, 6047. Vega Angew. Chem., Int. Ed. Eng. 1980, 19, 929.

? Baeyer-Villiger and Related Reactions
Ref: Comprehensive Org. Syn., Vol. 7, 671-688. Org. React., 1957, 9, 73; 1993, 43, 251.

O R R1 O R
2

O O H

O R O

R

1

NaOH

O R
1 OH + R OH

Baeyer,Villiger Ber., 1899,32, 3625; 1900, 33, 858.

Baeyer, 1905 Nobel Prize in Chemistry

Mechanism: Peracid nucleophilic addition reaction
O R R1 O R2 O O H R R
1

OO O O R
2

O R O

O R1 + R2 O-

a.

Alkyl group that migrates dose so with retention of configuration

b. The more electron-rich (most substituted) alkyl grou migration in preference (in general). t-alkyl>s-alkyl >benzyl>phenyl>n-alkyl>methyl Mehtyl ketones invariably provide acetate.

--Examples:

O

O PhCO3H
CHCl3, 25 C
o

O 71%

O CHO

PhCO3H
X X

OH

O +
O X

H

X=H X=OCH3

90% 19%

0% 73%

CH3CO3H 2h, 25 C, 88%
o

O O O
--Nucleophilic attack from least hindered exo face --Most substituted (electron-rich) carbon migrites

O R O O Rm .. R migrating C-C bond and O-O bond be trans-antiperiplanar O . . OO O

H

O

CH3CO3H 5d, 25 C, 94%
o

O

O

O

OO O O Trans-periplanar bond

? Benzylic Hydroperoxide Rearrangement --Alternative to Baeyer-Villiger reaction
Would be oxidized by Peracid

BF3.OEt2, H2O2

N H R OH O +

R O O
+

N+ BF 3 H H

OH

N H

RLi NaBH4 Boger, Coleman J. Org.Chem., 1986, 51, 5436. J. am.Chem.Soc., 1987, 109,2717. Tetrahedron Lett., 1987, 28, 1027.

BF3-

Boger, Yohannes J. Org. Chem. 1987, 52, 5283.

Urea-H2O2

a safe alternative to H2O2
O+N N+ OS O O S O
OH

O O

N N

O Ph Ph

O

O NH2 H2O2
6 6

O

O

OH OH O O O

H2N

O OMe O O O O O

O

OMe

? Beckmann Rearrangement and Related reaction
----- An analogous reaarangement reaction can be utilized to prepare lactam and amide 1. Beckmann Rearrangement
O O N S O Ph
12h, 0 C H2O
o

Beckmann, Ber, 1886, 89, 988.

H N
+

O

H

H N

O

-- Prepared from the oxime. --A wide range of leaving groups and catalysts have been utilized.

a. Group anti to oxime leaving group migrates. b. The alkyl group migrates with retention of configuration.

2. Curtius rearrangement
O RCO2H R N3 R N=C=O

Curtius Ber., 1890, 23, 3023.
H RNH2 or R N O

H2O or R'OH

O

R'

--(PhO)2P(O)N3 (DPPA), direcy conversion of carboxylic acids to acyl azides

--R group migrates with retention of configuration.
MeO2C HO2C Br N CO2Me Me MeO2C N CO2Me Me

DPPA, Et3N C6H6, reflux 72%

H2N Br

X

CO2H

DPPA, Et3N tBuOH

X

NHBOC

OBn

OBn

3. Hofmann Rearrangement
O R NH2
N N

Hofmann, Ber. 1881, 14, 2725

O R N H
CONH2 OTBS OMe

O Br R N
-

Br

O=C=N R

N

NaOBr, CH3OH
-40 C, then 60 C >80%
o o

N

NHCO2Me OTBS

OMe

-- Reagent employed include basic hypohalides: Pb(OAc)4, PhI(O2CCF3), PhIO -- R group migrates with retention of configuration.

4. Schmidt Reaction A. Conversion of Ketones to Amides
O R HN3 R Protic or
Lewis Acid Catalyst

R R

OH

H2O
+

N -H2O R + N N R H

N N

N

-H

+

O R N R H

tautomerization

--Most studies of Schmidt variants, similar to Beckmann rearrangement. --Asymmetric Variant utilizes chiral alkyl azide donors which provide products in high diastereoselectivity.

-- Bicycle ketone slightly favor migration of less substituted group, opposite of beckmann.
-- Reactivity: dialkyl ketone >alkyl, aryl ketone>diaryl Ketone >Carboxylic acid or alcohol

O Bn CO2Et

NaN3, 2.5 equiv MeSO3H, 9equiv. CHCl3, reflux, 83%

O NH Bn CO2Et O NH

>95% ee
O OH N3 BF3.OEt2 NaHCO3, 9equiv. PCC NaH, THF 57% Bu-t
t

+

Bu

B. Conversion of Carboxylic Acids to Amines
O R OH + HN3
H Cat.
+

R N=C=O

H2O

R NH2 H

O R OH

H

+

R

O+ + HN3

O R N=N+=NR

O N N+ N

R NH2

R N=C=O

-- Acid catalyst usually H2SO4, PPA, TFA-TFAA, or some Lewis acid.
--Good results when R=alkyl, hindered alkyl or aryl. -- Advantage in process length over Hofmann and Curtis rearrangements, but more drastic conditions.

H CO2H NaN3, H2SO4 Me CO2H
CHCl3, 76%

H NH2 Me NH2

C. Conversion of Aldehydes to Nitriles
O R H + HN3
H+ Cat.

R

N

--Acid catalyst usually H2SO4, can be Lewis acid. -- Schmidt reaction is the usual byproduct under these conditions to provide formamide. --More common method is to conversion aldehyde to oxime with hydroxylamine, followed by dehydration
-- Aromatic aldehydes are good substrates.
O NaN3, SiCl4 MeCN, 50% N H MeO HO CHO MeO NaN3, H2SO4 Br N H CN NC

Br

70%

HO

5. Lossen Rearrangement
O R
1

O N H OH
RX
2

O N H OR
2

R

1

Base

R

1

- OR2 N

-OR2

R1 N=C=O

Hydroxamic Acid preoared readily from carboxylic acides, ester or acyl halides

--R X usually AcCl, ArSO2Cl, RPO2Cl --rate of reaction proportional to the acidity of leaving group conjugate acid. -- R migrates with retention of configuration
1

2

O F F O H O O H O N O S O
NaOH, H2O 80%

O O- H3N+OH NH OH
TsCl NaOH, H2O 80%

F F

OH NH2 H NH2 H OH O

? Olefin Osmylation (Dihydroxylation)

First use: Criegee Justus Liebigs Ann. Chem. 1936, 522, 75. Milas J. Am. Chem. Soc. 1936, 58, 1302.

Mechanism

Scope

Comprehensive Org. Syn., Vol. 7, pp 437–448. Chem. Rev. 1980, 80, 187.

? OsO4 is an electrophilic reagent, and it behaves as a large reagent.

? Strained, unhindered olefins react faster than unstrained, sterically hindered olefins.
? Electron-rich olefins react faster than electron-deficient olefins. ? Diastereospecific, with attack on the C=C from the least hindered face.

- but OsO4 is expensive, volatile, and toxic
- various improvements:

-Alternative reagents to OsO4: KMnO4: Synthesis 1987, 85. Yields rarely as high as OsO4 but less hazardous and less expensive especially for large scale RuO4 or RuO2–2H2O/RuCl3–H2O + cooxidant More vigorous than OsO4 and olefin cleavage is observed

Diastereoselectivity
a. Endocyclic Olefins

b. Acyclic Systems

- Also observed with allylic ethers

- Higher diastereoselectivity of Z vs. E isomer implies eclipsed conformation important.

c. Exocyclic Olefins

Vedejs J. Am. Chem. Soc. 1989, 111, 6861

d. H-Bonding and Directed Dihydroxylation

Diol Stereochemistry Comparision
m-CPBA

OsO4

Via Bromohydrin

--Epoxidation on most hindered face of olefin(to gve different epoxide from m-CPBA). --trans diaxial ring opening (to give same hydrolysis product as from m-CPBA oxidation)

Prevost Neighboring Group Participation trans-diol Compt. rend. 1933, 196, 1128. Woodward

cis-diol
J. Am. Chem. Soc. 1958, 80, 209.

? Asymmetric Dihydroxylation reaction catalyst by OsO4 and related Reagents
1. Catalytic Methods

Corey J. Am.Chem. Soc., 1987, 109, 6213.
Ph NH Ph HN

C2-symmetry in ligand

Good or excellent selectivity
R1 R 74~93% ee R
2

R

2

R1 94~99% ee

R3 R2

R1 84~93% ee

82~88% ee

Poor selectivity
O R2 R1 R1 R2

R3 R1

? Shapless Catalytic Asymmetric Aminohydroxylation (AA)
O S O

a. Sulfonamide variant
-?,?-unsaturated esters:

Cl N Na

R

-?,?-unsaturated amides:

reaction works well without a ligand.

Cl

b. Carbamate variant
-?,?-unsaturated esters:

RO O

N

Na

-Styrenes:

c. Amide variant
R O N H Br

? Oxidation of Alcoholks
Collins reagents: CrO3-py2, alkaline oxidant Jones Reagents: CrO3 in aq. H2SO4/acetone Pyridinium Chlorochromate (PCC)

Chromium-based Oxidation Reagents

O HCl + CrO3 + Pyr. O Cr OCl.

H N+

Pyridinium Dichromate (PDC):
H N+ . Cr2O722

H2O + CrO3 + Pyr.

MnO2

Activated MnO2

KMnO4 / H2SO4

Manganese-based Oxidation reagents

KMnO4 / t-BuOH-5% NaH2PO4 aq. buffer

R4NMNO4

Cu(MnO4)2-6H2O and Ba(MnO4)2

Other Oxidation Reagents
NaOCl / NaClO2

m-CPBA / NaIO4
Ag2O / Ag2CO3 Dess-Martin oxidation
AcO OAc OAc I O O periodinane HO I O IBX O O

Nitroxide

Openauer Oxidation: Cl3CCHO, Al(OiPr)3

Chapter 8

Reduction Reactions

Introduction and Review
1. Conception and Classification Reduction
? 有机化合物中碳原子总的氧化态(oxidation state)降低的反应. ? 有机分子增加氢或/和减少氧的反应.

催化氢化

根据所采用 的方法分类

氢负离子还原
溶解金属还原

分类
根据反应前后物质 结构的变动分类 氢解反应 加氢反应

2. Catalytic hydrogenation 2.1 Heterogenous hydrogenation
(非均相催化氢化 / 多相催化) ? 非均相催化 催化剂: Pt, Pd, Raney-Ni, Pt, Pd:

吸附在载体上,如: C, CaCO3
特点:活性高,根据底物不同,可在常温,常压下反应; 也可在高温、高压下反应。 缺点:很贵, 含硫化合物会使其中毒失活

不同功能团氢化难易程度 Functional group Hydrogenation products RCOCl RCHO RNO2 RNH2 RC CR RCH=CHR (Z-) RCHO RCH2OH RCH=CHR RCH2CH2R RCOR RCH(OH)R ArCH2X ArCH3 RC N RCH2NH2
RCO2R’ RCONHR’
R



RCH2OH + R’OH RCH2NHR’
R



2.2 Homogenous hydrogenation (均相催化氢化)
催化剂: Rh 或 Ru的络合物

常用: (PPh3)3RhCl
(PPh3)3RuClH 优点

(TTC)

1) 均相反应,溶解度好,收率明显提高,室温、常压反应; 2)立体选择性高;

3)有硫化物存在不会中毒失活;
4)改变不同的配体,可得到不同性能的催化剂,前景广阔。

3. Metal hydride reduction
Metal hydride 亲核性氢负离子还原剂 LiAlH4 NaBH4

Solvents for metal hydride reductions
No. Metal hydride Solvent

1.
2. 3. 4. 5. 6. 7.

LiAlH4
LiAlH[OC(CH3)3]2

Ether, THF, diglyme
THF, diglyme

NaAlH2(OCH2CH2OCH3)2 [RED-Al] Ben, Tol, Xylene NaBH4 NaBH3(CN) LiBH4 AlH3 W, ethanol, diglyme W, methanol, DMSO THF, diglyme Ether, THF

8.

AlH[CH2CH(CH3)2]2 [DIBAL-H]

Toluene, DME

Products of metal hydride reductions
Reducing agent _________________________________ Reduction RCHO RCOR RCOCl Lactone Epoxide RCO2R' RCO2H RCONR2 RC N RX RC CR RCH2OH RCH(OH)R RCH2OH diol alcohol RCH2OH + R'OH RCH2OH RCH2NR2 RCH2NH2 RNH2 RH RCH=CHR(Z) 1 V V V V V V V e V f V 2 V V a X X d X X X X X V 3 V V V V V V V V X 4 V V V b b b X X X X X X X X X X X X V 5 V V 6 V V V V V V V X X X X 7 V V V V V V V V V X X V a a X a c 8 V V

RNO2

a. Reduction proceeds to the aldehyde stage only; b. very slow reaction c. Reducton proceeds to lactol stage only; d. phenyl esters give aldehydes. e. Some amides are reduced to aldehydes; f. where R is aliphatic; if R is aromatic, Azoarenes are formed; g. X= halogen or OSO2R’.

金属氢化物与Lewis Acid 配合后,还原活性变化 Boron regents Boranes

3NaBH4
H H2B H

+

4BF3

2B2H6 + 3NaBF3

BH2

+ 2

O O

BH3

亲电性氢负离子还原剂 ----- 易还原羧基

------易还原双键 -----hydroboration

硼烷还原的功能团
O C COOH CH CH C O CHO C N
C O C

CH2OH O (CH2)n CH2OH CH2OH ROH nr nr nr

CH2OH CH2 CH2 CHOH CH2NH2 CH C OH CH2OH

(CH2)n CH2 COOR COOCOCl NO2

Selectivity: reagent, solvent and reaction condition Asymmetric reduction: chiral reducing agents

4. Dissolving metal reduction(溶解金属还原 )
Active metals: Li, Na, K, Mg, Ca, Zn, Sn, Fe Proton donor: water, ethanol, acid
A B e A A + + B B e A + B 2H+ AH + BH

氢解

A A
A A B B e H
+

A

B

2H+

H A

B H H+

A

B

e

氢化还原

A

BH

e

A

BH

H A

B H

B A A

B

2H+

HB A A

BH

e.g.

Reduction of carbonyl group, three types of product
C O
Zn/HCl Na/EtOH Mg/Hg

CH2
Clemmensen reduction

C CHOH

C

OH OH
Bimolecular reduction

C O +

M

C O - M+
ROH

C OC

C OH
+

2M+

C OH
H
+

M

C OH

C

OH OH

CHOH

----Topic one

Confoemational Analysis & Stereochemistry of Hydride reduction reaction of Carbonyl Groups
A. Conformational Effects of Carbonyl Groups on Reactivity
O H H SP2 SP3 109.5o
Dihedral o angel 4

O H Hax Eclipsed conformation of carbonyl group

120o introduces torsional strain

This torsional strain accounts for the increased reactivity of six-membered ring cyclic ketone over acyclic ketones.

H

The addition to cyclohexanones is favorable

H

O Nu-

H H

( )

OH Nu

the torsional strain

1,3-diaxial interactions

1. Reversible Reactions

O HCN

HO

CN

cyclohexanone Keq for _____________ ~ 70 acyclic ketone
Thermodynamically more favorable for cyclohexanone
Torsional strain Effect of SP2 hybridization

2. Irreversible Reactions

O LiAlH4

HO

H

cyclohexanone rate (K) for _____________ ~ 335 acyclic ketone
One can selectively reduce a cyclic carbonyl in the presence of an acyclic carbonyl: under kinetic or thermodynamic conditions.

Synthetic consideration

B. Reaction of Carbonyl Groups

- Each reagent will display competitive reactions among the three primary pathways. Nature of each reagent and the nature of X will determine the course.

C. Reversible Reduction Reactions: Stereochemistry
O
i tBu

OH Al O PrOH OH
tBu

+

3

+
95%

tBu

5%

--Meerwein-Pondorff-Verley Reduction

Reversible Reduction

The reverse reaction is Oppenauer Oxidation

Mechanism: reversible intramolecular hydride transfer
O Al H H H
tBu

O O axial H delivery
-

H
tBu

H

H O

Al

O Al
tBu

Al Equatorial H delivery
tBu

O H H H

O

H H H

O

( )

Steric interaction

--Since it is freely reversible, one obtains the most stable alcohol from the reduction. The reaction is driven to completion by use of excess reagent and by distilling off the acetone formed in the reaction.

D. Irreversible Reduction Reactions: Strereochemistry 1. Cyclic Ketones
H
tBu

H

O LiAlH4 H H
tBu

H

H

H OH

H
tBu

H

OH H H H

+
H H 90 :

10

Nearly the same ratio obtained under these kinetic and above thermodynamic conditions.

H H

H Al H H O Li Li

1,3-interaction

--Difference in the relative rates: 1, 2-interactons slow the equatorial addition by a factor of ~10.
--LiAlH4 = small reagent
H Al H H

) (
H

tBu

H H ) ( 1,2-interaction

H

Favor axial hydride delivery

--1, 3-interactions are more remote(i.e. smaller), when compared to the 1,2-interactions (larger).
-- The destabilizing 1, 3-interactions increase as the size of the reagent increases or with the size of the 1, 3-diaxial substituents while the 1, 2-interactions are not nearly so sensitive to the size of reagents or the size of the substituents.
-

Small H reagent H H R H H O
-

Large H Reagent

Examples:
Me Me Me H H O LiAlH4 Me Me H H 45 Me OH H Me Me H OH Me : 55 H H

+

Increased steric hinderance of the 1, 3-diaxial interactions (Me/reagent) make axial hydride delivery more difficult. Me Me O LiAlH4 H H H H H H 100 : Me Me OH H Me Me H OH

+
H 0 H H

Serious 1,3-interactions preclude axial delivery of the hydride, but the axial Me'shave not effect on the 1,2-interactions. Me Me Me H H O Reagent Me Me H H 52-63 55-64 92-98 : : : Me OH H Me H OH Me 37-48 36-45 2-8 H H

+

Me

LiAlH4 NaBH4 LiAl(OMe)3H

Large reagent: greater selectivity for equatorial H- delivery.

Effect of the size of the reagent:
B H- K+ H
t-

H
t-

H

O Bu

H

H OH H H 3.5

H

OH H H H H

Bu H H

+ Bu
: 96.5

t-

Much large reagent !

Comparison of Diastereoselectivity of Hydride reducing reagents.
Me O
t-

Me

O Me Me

Me

O O Me O

Bu

Me

Reagent NaBH4 LiAlH4 LiAl(OMe)3H LiAl(OtBu)3H

%axial OH 20 8 9 9

% axial OH 25 24 69 36 98 >99 13

% axial OH 58 63 92~98 95 99.8 66

% endo OH 86 89 98 94 99.6 >99 -

% endo OH 14 8 1 6 0.4 no reaction -

(sBu)3BHLi 93 (Me2CHCHMe)3BHLi >99 LiMeBH3 2

Origin of Diastereoselectivity
yes H no

()
H O no yes

Steric interactions

The direction of attack is not from the axial or equatorial vector, but with a 109.5o approach of the nucleophile.
Torsional Strain

H H

Eclipsed conformation

90o R O R versus

_ 109.5 o(105o + 5o)Dunitz R R

angle Tetrahedron 1974, 30, 1563.

Good overlap and good approaches bond Angle required of SP3 hybridization. Better O ?-?* overlap for nucleophilic addition.

--Cyclic Ketones: Steric vs. Torsional interactions
NuHa He He Ha Ha

) (
O He

--As the nucleophile gets larger, this steric interaction with the C3-axial H gets worse-equatorial approach becomes the preferred line of attack. -- For C2 and C6-H substituents, this torsional interaction is worse than the steric interaction of Nu-/ C3 and C5-H’s (for small, unhindered Nu-)

Ha

Ha

Nu--All H- reduction have transition states that resemble rectant geometry.

--Diastereoselectivity is influenced by: a. Steric interactions (1, 3-diaxial interactions); b. Torsional strain (1, 2-interactions); c. Remote electronic effects (electrostatic interactions).
-- In contrast to early theories of ―product development control‖ / late transition state vs ―steric approach control‖ / early transition state.

Examples:
Nu-

) (
?-face O ?-face H H major

CH3

--locked trans diaxial ring fusion --preferential axial delivery of reagent.
LiAlH4

CH3 HO H H H 70~90%

--equatorial OH is major product --addition of Nu- from ?-face (equatorial delivery) suffers from repulsive interaction with axial Me.

Nu-

--vs
?-face O ?-face

) (
H major

CH3
LiAlH4

CH3 HO H H H

single 1,3-diaxial interaction

major product

--but
?-face ?-face O

) (

HCH3
Large H /CH3
-

OH

CH3

interaction H- major H- major

H

H

CH3
smaller H /CH3
-

H interaction

CH3

O

HO

2. Acyclic Carbonyl Groups

Review: Comprehensive Org. Syn., Vol.1, 49~75.
--Cram’s Rule
J. Am. Chem. Soc., 1952, 74, 5828.

Empirical and no mechanistic interpretation is imposed on model.

J. Am. Chem. Soc., 1959, 81, 2748. (cheletion-controlled addition)

--Prelog

Helv. Chim. Acta, 1953, 36, 308. (1,3-inducton)

-- Felkin (or Felkin-Ahn) model
Tetrahedron Lett., 1968, 2199, 2205 Tetrahedron Lett., 1976, 155, 159. Nouv. J. Chim., 1977, 1, 61.

a. Cram’s Rule

O S M S

OM

Nu-- Empirical Model

R L

Nu

L

R

-- Large group L eclipsed with R and not the carbonyl, Nuapproach from side of small (S) group. -- Stereoselectivity observed usually modest.

b. Felkin-Ahn Model

--Large group (L) trans antiperiplanar to forming bond.
the sterically next most demanding substituent is gauche to carbonyl

O L R

versus S NuM

O M L Nu S

-

OL R

O

L

( )

M

S

( )

M Nu

R S
minimizes torsional strain in transitionstate

R

sterically most demanding group is perpendicular to the plane of the carbonyl, anti to incoming nucleophile

--L is either the largest group (sterically) or the group whose bond to the ?-carbon
provides the greatest ?-?* overlap (e. g. halide, alkoxy group).

-- computational studies of Ahn confirmed this is the most stable transition state and extended it to ?-chloroketones. In the latter case, this minimized destabilizing electrostatic interactions between the halogen (electronegative group) and the incoming nucleophile.

Felkin-Ahn Model
M O L Nu
-

O versus L

S

S R R

M

) (

Nu-

Nu

-

O

Nucleophile prefers approach that minimizes torsional Stain and incorporates Burgi-Dunitz trajectory.primary Interaction is now between the Nu- and the small or medium substituent.

O O Cl O

O MeMgCl -75 C, THF
o

HO Me

O H Cl 92%

O
Me H

O O

Cl O R Et H Me
-

Cl
HO Et HO

R Et Me HO H Cl Et R Me O R H Et

R

Me

H

H

Me

Cl

Johnson, J. Am. Chem. Soc., 1968, 90, 6225.

c. Comparative Examples of Diastereoselection
Me SiMe3 R O Me NuR Me3Si Nu OH Bu4NF Me Nu R OH
n-

Me + R HO Bu SiMe3

Felkin Product Me R O R = Ph R = Ph R = Ph R = Ph R= BuLi MeLi
n

Me H Nu
-

--Diastereoselection depends on the size of the ketone substituent

+ Form 1 >100:1 >40:1 >100:1 11:1 >30:1 >100:1 >30:1 11:1 15:1 21:1 >100:1 3.5:1

Nu R OH Form 2 5:1 4:1 2:1 1.7:1 1.6:1 1.9:1 1:1 2.5:1 3.5:1 2:1 1.5:1 2:1

SiMe3 MgBr

O L R

BuLi MeLi

M L S Nu
-

O

M
S Nu

SiMe3 MgBr

R=

n

BuLi MeLi
SiMe3 MgBr

SiMe3
Increase size, increase diastereoselectivity

Me Ph O

R

ratio 74:26 76:24 83:17 98:2

R Ph

Me

R OH

Me Et i Pr t Bu

--Diastereoselectivity depends on size of nucleophile
Me Ph O LiAlH4 (sBu)3BHLi Me NuPh OH 74 >99 26 <1 Me Me Me + Ph OH Me

d. Chelation-controlled addition 螯合控制 羰基 ?,?-位 羟基、氨基、烷氧基,金属离子,螯合成环
--Review: Acc. Chem. Res., 1993, 26, 462.
Met XO NuOMet X S Nu

S

R

L

LR Can usually provide excellent diastereoselectivity Nu OR OH

1,2-chelation X= OH, OR NuR S R L Nu- H RL R Rs R O O Met syn-1,3-diol OH Rs R O O R L Met S

RL Nu OH R axialdelivery on most stable chair-like transition state.

1, 3-chelation

--Examples of 1, 2-chelation-control
H O O O O O R MeMgBr H O O HO R

> 95:5

Me
H O O HO

---to invert the stereochemistry
H O O O R

R

Nicolao, J. Am. Chem. Soc 1980, 102, 6611.

Me
BrMg O O

Me

Zoapatanol
CH3 O O H O OTBS Ph O H O MgBr CH3 OH OTBS

Monensin
Ph

50:1 stereoselectivity

Still, J. Am. Chem. Soc., 1980, 102, 2117, 2120

--Note that non chelation-controlled addition exhibit relatively modest stereoselectivities, but chelation-controlled addition can exhibt very good stereocontrol.

H BnO O O Met

H MeMgBr BnO OAc

H O

H

Me
H Nu O HO

OH

OAc

H R O O

Nu-

R

Met

R = CH3 Ph Ph Ph CH3
Met O O Nu-

Nu- = PhMgI 100:0 MeMgBr or MeLi 100:0 LiAlH4 84:16 (sBu)3BHLi (sBu)3BHLi
O

Two modles predictation

100:0 78:22
R O H H Nu Felkin model predicted product O OH

Nu H

O

OH

R

H R

R Chelation-controlled product

Nu-

Chelation Modle

Felkin Model

螯合离子及溶剂的影响
H O O O O C7H15
n

H

BuM
o

C7H15

H

C7H15 Bu

MEMO HO Bu

-78 C

+ I

MEMO OH

II Solvent pentane CH2Cl2 Et2O THF I 67 75 50 41 II 33 25 50 59

M=MgBr

Solvent pentane CH2Cl2 Et2O THF

I 90 93.5 90 100

II 10 6.5 10 0

M=Li

Me Nu
-

Me C7H15 RO

H O

H

Nu-

O

M Chelation model

R

O

C7H15

Felkin model

Li+; THF

?-烷氧基取代基的影响
H RO O C7H15
H
n

BuMgBr
o

C7H15

RO HO Bu

THF, -78 C

R = MEM MOM MTM CH2Ph CH2OCH2Ph THP

>99:1 >99:1 >99:1 99.5:0.5 99:1 75:25

Still, Tetrahedron Lett., 1980, 21, 1031.
H RO O R = CH2Ph R = TBS C7H15 Nu
-

H RO

C7H15

-78 C MeMgCl MeLi MeMgCl
MgCl

o

HO

Bu

Et2O THF Et2O THF

>99:1 60:40 60:40 10:90

chelation-controlled

Felkin addition

Reetz, J. Chem. Soc., Chem. Commun., 1986, 1600.

还原产物的立体控制
OH R1 O versus OTBS R1 O
HO K-selectride R OBn THF, -95 C R
o

OH
Zn(BH4)2

R

2

Et2O, 0 C

o

R1 OH

R2

anti-1, 2-diol chelation-controlled addition

OH
1. Red-Al, o toluene, -78 C 2. Bu4NF

R1 OH
O

R

2

R2

syn-1,2-diol Felkin addition
HO

Zn(BH4)2 OBn Et2O, -30 C
o

R

OBn

90:10 Felkin addition

95:5 chelation-controlled

-- 1, 3-Chelation-Contralled Additions (?-chelation-controlled addition)
L O Chelation control with external H delivery H R' HH O R'' O

M

L O R''
L M L

HOH R' OH R''

H R'

OH O R''
controlled with interal H delivery

R'

Syn-1,3-diol

H R'

O O R''

L B L H
R'

OH

OH R''

anti-1,3-diol

R3B/NaBH4, Et2BOCH3-NaBH4 in THF-MeOH Dibal-H (>98:2)
Tetrahedron, 1984, 40, 2233; Tetrahedron Lett., 1987, 28, 155; 1986, 27, 3009.

Aluminum Hydride Reducing Agents

less reactive, more selective

- Examples:

Borohydride Reducing Agents

Hydride Reductions of Functional Groups

Reactions of Borane (BH3)

Characteristics of Hydride Reducing Agents ? NaCNBH3

? LiBH4

? Zn(BH4)2

Review: Narasimhan Aldrichim. Acta 1998, 31, 19.

? NaBH4/CeCl3 (catalytic amount (0.1 equiv))

- Readily enolizable carbonyl can be reduced.

clean addition, no enolization Imamoto J. Am. Chem. Soc. 1989, 111, 4392.

Luche J. Am. Chem. Soc. 1981, 103, 5454; 1978, 100, 2226.

Reagent comparisions for 1,2- vs. 1,4-reduction

? NaBH4–CoCl2
Selective reduction of nitriles.

- Good for 1,2- vs. 1,4-reduction.

Garner Org. Syn. 1992, 70, 18.

Asymmetric Reductions
SP2 杂化碳 ?烯烃双键的不对称催化氢化

?羰基化合物的不对称还原
?亚胺的不对称还原

?不对称氢转移反应

?碳碳双键的不对称催化氢化

CO2H R NHAc

H2
Chiral Rh Catalyst

* R

CO2H

NHAc

手性二磷配体的设计策略: 活跃的研究领域

* P R' R'' R''' R'

P R'' * R
R'

* P R'' R*

用于催化不对称氢化反应的手性膦配体
R PPh2 R N PPh2 DEGHOS R DuPHOS PPh2 PPh2 PPOPHOS c-C6H11 PPh2 MeO PPh2 CYCPHOS (R, R)-DIPAMP P P OMe Ph2P PPh2 PPh2 PPh2 NORPHOS Fe N(CH3)2 PPh2 PPh2 BPPFA Me P P R R Ph PNNP Ph N PPh2 N PPh2

Me

(S, S)-CHORAPHOS

Ph2P PPh2 PPh2 O N CO2Bu-t (R)-BINAP PPh2 PPh2 (R, R)-DPCP (S, S)-BPPM PPh2 Ph2P PPh2 O

DIOP PPh2

PPh2 PPh2 (+)-DIPMC

PPh2 (2R, 3R)-NORPHOS

PPh2 PPh2 (-)-MENO

Me

N OPPh2

Me OPPh2

Me PPh2

N

Me PPh2

R Me

P

P

Me R

Me
i

P

P

Pr

Pri Me

N P P

R = c-C5H9, c-C6H11, tBu, CEt3, 1-adamantyl BISP* X X O O Ph2P PPh2 (R)-BIPHEMP, R=Ph, X=Me (R)-BIPHER, R=c-Hex, X=Me MeOBIPHEP, R=Ph, X=OMe P N P O O

1、烯酰胺的不对称氢化 潜 (前)手性 Prochirality

CO2H R NHAc

H2, Rh(II) Chiral ligand R

*

CO2H NHAc

烯酰胺/ Rh complex /H2

?-氨基酸

CO2H R
磷配体

H2, Rh(II) Chiral ligand R

*

CO2H NHAc

NHAc

e.e% 构型 R=Ph R=H 94(S) 91 (R) 96(S) 99 (R)

(R,R)-DIPAMP (S, S)-CHIRAPHOS

(S, S)-NORPHOS
(R, R)-DIOP (S, S)-BPPM (S)-BINAP (S,R)-BPPFA

95(S)
85(R) 91(R) 100(R) 93(S)

90(R)
73(R) 98.5(R) 98(R)

(S,S)-SKEWPHOS
(S,S)-CYCPHOS (S,S)-Et-DuPHOS

92(R)
88(R) 99(S) 99.4(S)

Catalytic Mechanism
P * P

Halpern, Brown, 1980
Rh k-1' S S + H Ph CO2H NHAc k1'' k-1'' H N Me Ph O k2'' [H2] + H N Me Ph O k3 ' COOMe P H * Rh P H S + COOMe Rh P P * +

MeOOC

H N Me Ph O k2' [H2]

k 1' +

螯合

P * P

Rh

吸氢

MeOOC P H * Rh P H k 3' S

H N Me Ph O

k3'

S

k 3'

S

Me

Me S COOMe Ph S MeOOC Ph HN O Rh P * P H

负氢转移
P H *

O Rh P k4'

NH

-[Rh(P * P)S2]+

k4' -[Rh(P * P)S2]+ H H MeOOC N Ph O

还原脱除
Me O H H N COOMe Ph Me

螺环瞵配体
Ph2PO H OPPh2 Ph2PO H OPPh2 H

H H (R, R)H (S, S)Ph2PO

OPPh2

(1R, 1'R, 2S, 2'S)-

手性双氨基瞵配体:

NHPPh2 NHPPh2

NHPPh2 NHPPh2

NHPPh2 NHPPh2

NHPPh2 NHPPh2

(R)-BDPAB

(S)-BDPAB

(R)-H8-BDPAB

(S)-H8-BDPAB

2、手性Rh-二茂铁基膦络合物催化的丙烯酸的不对称氢化
H CH3 N(CH3)CH2CH2R2 PPh2 PPh2 Me Me Rh-(R)-/(S)-1a Ar COOH H2 Ar H COOH CHMe2

Hayashi, Ito, 1987.

Fe

+

1a NR2 = N 1b NR2 = NBu2 1c NR2 =NEt2 1d NR2 = N
H Fe PPh2 CH3 N(CH3)CH2CH2R2 PPh2

2a Ar = Ph 2b Ar = 4-ClPh 2c Ar = 4-MeOPh 2d Ar = 2-naphthyl

3

R

Me Rh-(R)-/(S)-1a COOH H2

R Ar

H Me COOH

+
Ar

H

E-4a R =Et E-4b R =Ph

5

―增强底物功能团与手性配体之间的亲和性相互作用可以提高立体选择性” ―手性氨基二茂铁”

由手性二茂铁基瞵-铑配合物催化的三取代丙烯酸的不对称氢化
烯烃 配体 溶剂 时间(h) 产物 e.e.%构型

2a
2a 2a

1a
1a 1a

THF/MeOH (90/10)
THF/MeOH (80/20) i-PrOH

30
20 20

3a
3a 3a

98.4(S)
97.6(S) 97.0(S)

2a
2a

1a
1b

MeOH
THF/MeOH (80/20)

5
20

3a
3a

95.8(S)
97.9(S)

2a
2a 2b 2c 2d E-4a E-4b

1c
1d 1a 1a 1a 1a 1a

THF/MeOH (80/20)
THF/MeOH (80/20) THF/MeOH (80/20) THF/MeOH (80/20) THF/MeOH (80/20) i-PrOH THF/MeOH (80/20)

30
30 40 40 65 100 100

3a
3a 3b 3c 3d 5a 5b

98.1(S)
98.2(S) 97.4(S) 96.7(S) 97.3(S) 97.3(2S,3R) 92.1(2S,3R)

CHEt2 PPh2
Kang, 1998

Fe PPh2 CHEt2 (R, R)-FerroPHOS

[Rh(COD)2}BF3 / (R,R)-FerroPHOS / H2 / 2 atom, 20~30 oC

脱氢氨基酸, e.e. % ~99.9%
空气稳定性

3、钴络合物催化的?,?-不饱和酯的不对称氢化
CN

N R H

N R

1a R = CH2OSiMe2But 1b R = CH2OEt 1c R = CMe2OH 半咕啉型手性C2对称螯合配体

CH3 R' COOEt
NaBH4, 1mol% COCl2, 1.2 mol% 1a

CH3 R' * COOEt

2a R'= PhCH2CH2CH3 2b R' =
H 3C

3a R'= PhCH2CH2CH3 3b R' =
H 3C

2c R' = (CH3)2CH2d R' = Ph

3c R' = (CH3)2CH3d R' = Ph

?, ?-不饱和羧酸酯的对映选择性还原
底物
E-2a Z-2a E-2b Z-2b E-2c

产率%
97 95 95 94 84

e.e. (%)
94 94 94 94 96

构型
(R)-(+) (S)-(-) (R)-(+) (S)-(-) (S)-(-)

Z-2c
E-2d Z-2d

86
95 97

90
81 73

(R)-(+)
(S)-(+) (R)-(-)

4、开链烯醇酯的不对称氢化
中等程度的对映选择性

二烯基酯 (烯炔基酯)
OAc OAc R 1 CH3 Rh(I)/DuPHOS, THF, MeOH H yield 97% 2a R =n-C5H11, e.e.94% 2b R = Ph, e.e. 94% R 30 psi H2

P

P

DuPHOS
OAc 30 psi H2 R
Rh(I)/DuPHOS, THF or MeOH yield >97%

OAc CH3 R H R

OAc CH3 H

R = n-C5H11, e.e. 98.5% R = Ph, e.e. 97.8% R = CH2CH2OCH2Ph, e.e.>98%

Me Ar2

5、应用实例
Noyori, 1987.

O O Ru O O Me

P P Ar2

BINAP-Ru(II) 二羧酸络合物
Ru-(S)-BINAP
OH

Ru-(R)-BINAP
Me 拢牛醇
> 30 atm H2, MeOH, 20 C
o

OH

(R)-香茅醇 98% e.e. Ru-(S)-BINAP Me Ru-(S)-BINAP
OH

橙花醇

OH

(S)-香茅醇 98% e.e.

生物碱的合成:
MeO MeO NAc OMe OMe Ru-(R)-BINAP, EtOH, CH2Cl2, 23 C 4 atm, H2, 定量
o

MeO MeO NAc OMe OMe

Z-烯酰胺 萘普生的合成:

> 99.5% e.e.

Me CO2H Ru-(S)-BINAP, 135 atm H 2 MeO MeO
(S)-萘普生, Y 92%, e.e. 97%

CO2H

Me

Li/Et2NH

[Rh(R)-BINAPCOD] NEt2

+

NEt2 H2O/H+

月桂烯
Me CHO

N,N-二乙基橙花胺

(R)- 95% e.e.

Takasago Co., 1500 t/year

OH

(S)-Cotronellal
(R)-Citronellal 香茅醛 (-)-menthol 薄荷醇

维生素E, K侧链的合成:
Rh-(R)-BINAP

R
HO O

OH
O

R

R

OH

VE

O

VK

?羰基化合物的不对称还原
催化氢化/化学选择性, 金属氢化物还原 1、用BINAL-H还原 LiAlH4, NaBH4, BH3.THF 的活性与选择性的改造

手性配体修饰的金属氢化物 ——活泼氢数目减至最少,获得高度的化学选择性 ——手性配体的引入, 提高对映面的选择性
1951, 手性配体改造LAH

1979, Noyori, 手性联萘酚修饰 BINAL-H

O Al O

H

O

H Al

Li
OR'' O

OR''

Li

(S)-BINAL-H

(R)-BINAL-H

手性LAH还原剂: R, 温度的影响

R' H

R OH (S)-

R'
(S)-BINAL-H

R O

(R)-BINAL-H

R' HO H (R)-

R

产物的对映选择性可控!

S

O Al O O R''
优势构象

R Li C R' S O

S

O Al O O R'' Li O

R' C R R

非优势构象 n-?排斥

R’, R / 电性因素 / 立体空间因素

芳香酮的还原:
H (S)-

R (S)-BINAL-H OH O

R

(R)-BINAL-H HO

R

H

(R)-



BINAL-H 构型 产率%

产物 e.e.% 型 95 98 100 100 71 44 62

构 R S S S S R R

C6H5COCH3 C6H5COC2H5 C6H5CO-n-C3H7 C6H5CO-n-C4H9 C6H5COCH(CH3)2 C6H5COC(CH3)3 ?-Tetralone

R S S S S R R

61 62 78 64 68 80 91

炔基酮/烯基酮还原的立体选择性
R1 R2 H (S)OH
(S)-BINAL-H

R1 R2 O

R1
(R)-BINAL-H

R2 HO (R)H

R1

R2 H OH (S)-

(S)-BINAL-H

R1 O

R2 (R)-BINAL-H

R1 HO (R)-

R2 H

光学活性的烯丙醇/ 炔丙醇的制备
CH3OCO CO2CH3 O O HO H THPO CO2CH3 THPO H OH HO OH

OR

H

OH

(S)- , 100% d.e. (S)-, R=COPh, 98% d.e. (S)-, R=THP, 99% d.e. (S)-, R=H, 100% d.e.
X H OH

X = Br, 96% d.e. X = I, 97% d.e.

二烷基酮的对映选择性不高! 苄基甲基酮 2-辛酮 (S)-1-苯基-2-醇 e.e.% 13% (S)-2-辛醇 e.e.% 24%

S

O Al O O R'' Li O

R C R' S

S

O Al O O R'' Li O

R' C R R

R H

D OH (S)醛

(S)-BINAL-H

R O

D (R)-BINAL-H

R HO (R)-

D H

BINAL-H 构型 S S R R R

产率% 91 90 91 93 75

醇产物 e.e. % 91/84 72 88 82 82

构型 S S R R R

香茅醛-1-d 橙化醛-1-d E,E-法尼醛 1-d Z,E-法尼醛 1-d 苯甲醛-1-d

2、过渡金属络合物催化的羰基氢化

酮的不对称氢化 -----制备手性醇
BINAP-Ru(II)

PPh2 PPh2

PPh2 PPh2

(R)-BINAP

(S)-BINAP

O R NHBoC

O OC2H5

OH

O OC2H5

OH

O OC2H5

BINAP-Ru H2

R NHBoC

+

R NHBoC

threoa R = PhCH2b R = Me2CHCH2c R = Cyclohexylmethyl-

erythroOH S S NH2 COOH

Statin

底物

催化剂
RuBr2-(R)BINAP
RuBr2-(S)-BINAP RuBr2-(R)BINAP RuBr2-(R)BINAP

产物 产率% threo:erythro

a
a b c

97
96 99 92

>99:1
9:91 >99:1 >99:1

手性二醇:1, 2-, 1, 3- , 1,4- 二醇 / 制备手性配体 二酮的不对称氢化
Chan, 1997.
O O
Ru-(R)- or -(S)-BINAP HCl, H2

OH

OH or

OH

OH

(R, R)-

(S, S)-

yield > 95%, > 99.9% e.e.

BINAP-Ru(II)(OOCCH3)2

BINAP-Ru(II)(OOCCH3)2 / 2 CF3COOH
BINAP-Ru(II)(OOCCH3)2 / 2 HCl

增加酸性 引入配位杂原子

简单二烷基酮的还原一般选择性较低!
Noyori, 1995.
RuCl2-[(S)-BINAP](DMF)n, S,S-1,2-二苯基乙二胺 /KOH, isopropyl alcohol

O Ar R

OH
Ru(II)-Phosphine diamine KOH, (CH3)2CHOH H2, 4atm, 28 C, 6h
o

Ar

R

yield >99% 97% e.e

开发稳定、高效的催化剂:
O
P Cl * Ru P Cl NH2 NH2 *

OH

P Cl * P Ru Cl

NH2 * NH2

H2

94% e.e 100% yield

Zhang, 1998. -----弱碱能加速简单酮的Rh催化氢化反应
O
[Rh(COD)Cl2]2 lutidine, MeOH, 24h, 20 C r.t, 30 atm, 底物:[Rh(COD)2Cl2]:Cat = 1.0:0.005:0.01
H P Cl Rh P
OH

OH
PennPhos
o

H2 *

P Rh P S

Cl H
O

R P P R Me PennPhos

*

R

H

S
i

R = Me , Pr

RO-, B *

H P Rh P O S S Cl * P P

H Cl Rh O H

ROH, S or BH+

Rh-PennPhos体系催化简单酮的不对称氢化
反应 酮
O

Lutidine 当 量

KBr 当量

时间h

Yield %

e.e. %

1
O

0.4
0.4
O

_
_ 1.0 1.0 1.0 1.0 1.0 1.0

24
53 88 56 48 75 94 106

97
94 95 99 96 66 99 90

95
95 93 73 75 85 84 92

2 3 4 5 6 7 8
O O

0.8
O

0.8 0.8 0.8 0.8 0.8
O

O

O

9

0.8

1.0

96

51

94

3、硼杂噁唑烷催化体系 硼烷衍生物,硼杂噁唑烷: Chemzyme 化学酶 1981, Hirao; Itsuno; Corey, CBS催化剂 (Corey-Bakshi-Shibata)
H N Ph Ph O H Ph N 2 H NAP NAPN O
?

Ph O N

H Ph Ph B H 3 Ph O

H N O 4a R = H 4b R = Me B R

CBS 催化剂举例

B R 1a R= H 1b R = Me 1c R= Bu
?-

B H

Ph O Ph O N B Me 7

H

N

B R 5a R = H 5b R = CH3 5c R = n-Bu

B R

6a R = H 6b R = Me

2R1R2CO + BH3


(S)-1b,THF
1 min.,25 C
o

(R1R2CH O)2BH

R1R2CHOH

BH3当量

(S)-1b当量

产物构型(e.e. %)

C6H5COCH3
C6H5COCH3 C6H5COCH3 C6H5COC2H5 C6H5COC2H5

2.0
1.0 1.2 1.2 1.0

1
0.1 0.025 0.05 0.05

R(97)
R(97) R(95) R(86) R(88)

C6H5COC2H5
t-BuCOCH 3 t-BuCOCH 3

0.6
0.6 0.6 0.6 0.6

0.05
0.05 0.1 0.05 0.05

R(90)
R(88) R(92) R(89) S(97)

?-tetralone C6H5COCH2Cl

CBS催化反应机理:
H N Ph Ph O B Me OBH2 RL H H N H 2B H RS
-

H
BH3.THF

Ph

Ph O

N H 3B

B Me O RS RL

H Rs

OH RL

H Rs

Ph

Ph O

Ph

Ph N O BH3 Me H B B

O RL

B O+ RL

H

H Me RS

O O O O C5H11-n O O Ph O Ph O

10% 1b
0.6 eq. BH3.THF O H

C5H11-n OH

前列腺素合成, 酮基的选 择性还原; C-15 位的立体化学控制
OH I

82% e.e.
OH Cl yield >99% e.e. 94% H CH3NH2 >99% OH N H 1. NaH 2. F C
3

O Cl 0.6 eq. BH3.THF 1b

H

H NaI
97%~99%

Cl

H

O N+ H2Cl-

CF3

3. HCl

(R)-氟西汀

R

R O B NH

CH3 H 3C CH3 O N H B B H2 O H Ph CH3 Ph OH CH3

?-蒎烯衍生

O

B NH

(+)-1

(-)-1

CH3

底物
O Ph
O Ph
O Ph CO2Me

产物
OH Ph
OH

温度
0~5 25~30

时间h
4 4

产率%
95 93

e.e. %
92 81

Et
CH2Cl

Et

Ph

CH2Cl

0~5 25~30 0~5 0~5 0~5

1 1 6 2 2

93 96 65 >90 >90

76 90 59 93 37

OH Ph CO2Me

O Ph
Me(CH2)4

OH

Me
O Me

Ph

Me
OH

Me(CH2)4

Me

Brown, H. C., 1961. (+)-(Ipc)2BCl, (Ipc)2BH, IpcBH2

)2

BCl

BH )2

----仅对Z-烯烃显示极好的选择性

二异松莰烯基硼烷

Masamune, S. 1985. --反-2,5-二甲基硼杂环戊烷 DMB
---Z-/E-二取代烯烃、三取代烯烃

B H DMB
H OH N H R'=H, Me

非硼杂噁唑烷类催化剂
S H H2N Ph Ph OH S H H2N Ph Ph OH H R' R R

?-氨基醇类化合物

改良的LAH

实现酮的对映选择性还原
H N Ph

硼杂噁唑烷
手性配体配位的过渡金属催化

Ph B O

BCl )2

B Alphine-Borane Midland
O Al H

R Oxazaborolidines Corey

Icp2BCl Brown
Me Ar2 P Ru P Ar2 O O Me O O

B H Boralane (DMB) Masamune

O

Li OR''

BINAL-H Noyori

Ru-BINAP Noyori

?亚胺的不对称还原
亚胺的不对称还原制备手性仲胺与由酮制备醇同样重要 Burk, 1993. [Rh(COD)(DuPHOS)]+CF3SO3-

R P P R DuPHOS R R

N

H N O

Ph

EtO2C

Ph2P PPh2

(2S,4S)-BPPM/ BiI3/ H2

N CO2But

(2S, 4S)-BPPM
O

F F O

N

(2S,4S)-BPPM BiI3, H2

F F O

F

CO2H N O 左氟沙星 Me

NH
S

N

Me

Me

Me

N

Buchwald, 1992~1994 二茂钛催化剂:
活性高,空气稳定, 高对映选择性

S

F

Ti
S

F

?不对称氢转移反应
不对称氢转移还原:易于操作,不使用活性的金属氢化物或氢气

手性磷/手性氮配体 Noyori, 1997
Ts N Ru N H R R1

O R2 cat. Ru(II)
Me2CHOH

OH R2 R1 e.e. 99%
OH

1,3,5-三甲基苯, 甲基异丙基苯
O cat. Ru(II) NHCbz
Me2CHOH

OH

NHCbz (3S, 4S)-

NHCbz (3R, 4S)-

(R,R)-Cat. (S,S)-Cat.

97%, e.e. 99% 97%, e.e. 99%

简单的氨基醇作为手性配体:
O R1
R1
NH OH

OH R2
e.e. % 94 97 93 92

R2 0.25 mol % RuCl2 (p-cymene) R 1
2.5 mol % i-PrOK/i-PrOH

R2 Me Me Et n-Pr

时间h 1.5 1.5 1.5 1.5

n-Bu
n-C6H13

1.5
1.5

95
95

Recent Development of Asymmetric Reductions

A Metal-Free Transfer Hydrogenation: Organocatalytic Conjugate Reduction of ?, ? -Unsaturated Aldehydes**
Jung Woon Yang, Maria T. Hechavarria Fonseca, Nicola Vignola, and Benjamin List*

Received: August 28, 2004
Angew. Chem. Int. Ed. 2004, 43, 6660 –6662

Catalyst screening for the iminium catalytic conjugate reduction of ?, ? - unsaturated aldehydes.

Organocatalytic conjugate reduction of ?, ? - unsaturated aldehydes

Continue

Proposed mechanism of iminium catalysis

In summary, we have developed the first metal-free catalytic transfer hydrogenation. This novel iminium catalytic conjugate reduction of a,b-unsaturated aldehydes is highly efficient and chemoselective. It requires low catalyst loadings and tolerates various functional groups that are sensitive to the conditions of standard hydrogenations and alternative conjugate reductions.

Metal-Free, Organocatalytic Asymmetric Transfer Hydrogenation of Unsaturated Aldehydes**
Jung Woon Yang, Maria T. Hechavarria Fonseca, Nicola Vignola, and Benjamin List*

Received: October 26, 2004 Angew. Chem. Int. Ed. 2005, 44, 108 –110

Organocatalytic asymmetric transfer hydrogenation of ?, ? - unsaturated aldehydes.

Continue

Proposed mechanism of the organocatalytic asymmetric transfer hydrogenation.

Attractive features of this process

1) Its high yields, chemo-, and enantioselectivities;
2) Its enantioconvergence;

3) its simplicity and practicability.

Enantioselective Organocatalytic Hydride Reduction
Ste?phane G. Ouellet, Jamison B. Tuttle, and David W. C. MacMillan*

DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125 Received October 10, 2004;

J. AM. CHEM. SOC. 2005, 127, 32-33

EOHR: Enantioselective organocatalytic hydride reduction

Effect of Catalyst and Solvent on EOHR

Effect of Dihydropyridine Component on EOHR

Effect of Aldehyde Substituents on EOHR

Continue

In summary, we have developed the first organocatalytic hydride reduction, an operationally simple reaction that allows the enantioand chemoselective transfer of hydrogen from Hantzsch esters to geometrically impure enals.


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